JP2016512239A5

JP2016512239A5 -

Info

Publication number: JP2016512239A5
Application number: JP2016500120A
Authority: JP
Filing date: 2013-12-06
Publication date: 2017-01-26

Description

本発明の化合物は非常に強力なＡＴＲ阻害剤である。これらの化合物は、シスプラチンおよびゲムシタビンなどの他のがん用薬剤との併用療法において驚くべき相乗効果も示す。
一実施形態において、例えば、以下の項目が提供される。
（項目１）
式Ｉの化合物：

［式中、
Ｒ ^１およびＲ ^２は、Ｈ；ハロ；−Ｃ（Ｊ ^１） _２ＣＮ；−ＣＮ；Ｗ；またはＭから独立して選択され；
Ｊ ^１は、ＨまたはＣ _１〜２アルキルから独立して選択され；あるいは
２個出現するＪ ^１は、それらが結合している炭素原子と一緒になって、任意選択で置換されている３〜４員の炭素環式環を形成しており；
Ｍは、最大で３個のメチレン単位が、−Ｏ−、−ＮＲ−、−Ｃ（Ｏ）−または−Ｓ（Ｏ） _ｚ −で任意選択で置き換えられているＣ _１〜８脂肪族であり、各Ｍは、０〜３個出現するＲ ^２ａで任意選択で置換されており；
Ｒ ^２ａは、ハロ；−ＣＦ _３；−ＣＮ；Ｃ _１〜４脂肪族鎖であって、該脂肪族鎖の最大で２個のメチレン単位が、−Ｏ−、−ＮＲ−、−Ｃ（Ｏ）−もしくは−Ｓ（Ｏ） _ｚ −で任意選択で置き換えられているＣ _１〜４脂肪族鎖；または酸素、窒素もしくは硫黄から選択される０〜２個のヘテロ原子を有する３〜６員の非芳香族環から独立して選択され；
Ｗは、酸素、窒素もしくは硫黄から選択される０〜３個のヘテロ原子を有する３〜７員の完全飽和、部分不飽和もしくは芳香族の単環式環；または酸素、窒素もしくは硫黄から選択される０〜５個のヘテロ原子を有する７〜１２員の完全飽和、部分不飽和もしくは芳香族の二環式環から独立して選択され；Ｗは、０〜５個出現するＪ ^Ｗで任意選択で置換されており；
Ｊ ^Ｗは、−ＣＮ、ハロ、−ＣＦ _３；最大で２個のメチレン単位が−Ｏ−、−ＮＲ−、−Ｃ（Ｏ）−もしくは−Ｓ（Ｏ） _ｚ −で任意選択で置き換えられているＣ _１〜４脂肪族；または酸素、窒素もしくは硫黄から選択される０〜２個のヘテロ原子を有する３〜６員の非芳香族環から独立して選択され；
同一原子上に２個出現するＪ ^Ｗは、それらが結合している原子と一緒になって、酸素、窒素または硫黄から選択される０〜２個のヘテロ原子を有する３〜６員環を形成しており；あるいは
２個出現するＪ ^Ｗは、Ｗと一緒になって、６〜１０員の飽和または部分不飽和の架橋環系を形成しており；
Ａは、

から独立して選択され；
ｐは０、１または２であり；
Ｒ ^３は、−（Ｌ） _ｎ −Ｑ ^１またはＴから独立して選択され；
ＬおよびＴは、それぞれ独立して、Ｃ _１〜１０脂肪族鎖であり、該脂肪族鎖の最大で３個のメチレン単位が、−Ｏ−、−ＮＲ−、−Ｓ（Ｏ） _ｚ −または−Ｃ（Ｏ）−で任意選択で置き換えられており；各ＬおよびＴは、０〜５個出現するＪ ^ＬＴで独立して置換されており；
Ｊ ^ＬＴは、ハロ、−ＣＮまたはＣ _１〜４脂肪族鎖であって、該脂肪族鎖の最大で２個のメチレン単位が、−Ｏ−、−ＮＲ−、−Ｃ（Ｏ）−もしくは−Ｓ（Ｏ） _ｚ −で任意選択で置き換えられているＣ _１〜４脂肪族鎖から独立して選択され；
ｎは０または１であり；
Ｑ ^１は、酸素、窒素もしくは硫黄から選択される０〜３個のヘテロ原子を有する３〜７員の完全飽和、部分不飽和もしくは芳香族の単環式環；または酸素、窒素もしくは硫黄から選択される０〜５個のヘテロ原子を有する７〜１２員の完全飽和、部分不飽和もしくは芳香族の二環式環から独立して選択され；Ｑ ^１は、０〜５個出現するＪ ^Ｑで独立して、置換されており；
Ｊ ^Ｑは、ハロ；−ＣＮ；＝Ｏ；Ｑ ^２；またはＣ _１〜８脂肪族鎖であって、該脂肪族鎖の最大で３個のメチレン単位が、−Ｏ−、−ＮＲ−、−Ｃ（Ｏ）−もしくは−Ｓ（Ｏ） _ｚ −で任意選択で置き換えられているＣ _１〜８脂肪族鎖から独立して選択され；各々の出現するＪ ^Ｑは、０〜３個出現するＪ ^Ｒにより任意選択で置換されており；あるいは
同一原子上に２個出現するＪ ^Ｑは、それらが結合している該原子と一緒になって、酸素、窒素または硫黄から選択される０〜２個のヘテロ原子を有する３〜６員環を形成しており；２個出現するＪ ^Ｑにより形成された該環は、０〜３個出現するＪ ^Ｘで任意選択で置換されており；あるいは
２個出現するＪ ^Ｑは、Ｑ ^１と一緒になって、６〜１０員の飽和または部分不飽和の架橋環系を形成しており；
Ｑ ^２は、独立して、酸素、窒素もしくは硫黄から選択される０〜３個のヘテロ原子を有する３〜７員の完全飽和、部分不飽和もしくは芳香族の単環式環；または酸素、窒素もしくは硫黄から選択される０〜５個のヘテロ原子を有する７〜１２員の完全飽和、部分不飽和もしくは芳香族の二環式環であり；
Ｊ ^Ｒは、ハロ；−ＣＮ；＝Ｏ；→Ｏ；Ｑ ^３；またはＣ _１〜６脂肪族鎖であって、該脂肪族鎖の最大で２個のメチレン単位が、−Ｏ−、−ＮＲ−、−Ｃ（Ｏ）−もしくは−Ｓ（Ｏ） _ｚ −で任意選択で置き換えられているＣ _１〜６脂肪族鎖から独立して選択され；各Ｊ ^Ｒは、０〜３個出現するＪ ^Ｐで任意選択で置換されており；あるいは
同一原子上に２個出現するＪ ^Ｒは、それらが結合している該原子と一緒になって、酸素、窒素または硫黄から選択される０〜２個のヘテロ原子を有する３〜６員環を形成しており；２個出現するＪ ^Ｒにより形成された該環は、０〜３個出現するＪ ^Ｘで任意選択で置換されており；あるいは
２個出現するＪ ^Ｒは、Ｑ ^２と一緒になって、６〜１０員の飽和または部分不飽和の架橋環系を形成しており；
Ｑ ^３は、酸素、窒素もしくは硫黄から選択される０〜３個のヘテロ原子を有する３〜７員の完全飽和、部分不飽和もしくは芳香族の単環式環；酸素、窒素もしくは硫黄から選択される０〜５個のヘテロ原子を有する７〜１２員の完全飽和、部分不飽和もしくは芳香族の二環式環であり；
Ｊ ^Ｘは、ハロまたはＣ _１〜４脂肪族鎖であって、該脂肪族鎖の最大で２個のメチレン単位が、−Ｏ−、−ＮＲ−、−Ｃ（Ｏ）−もしくは−Ｓ（Ｏ） _ｚ −で任意選択で置き換えられているＣ _１〜４脂肪族鎖から独立して選択され；あるいは
Ｊ ^Ｐは、ハロ；−ＣＮ；＝Ｏ；Ｃ _１〜６脂肪族鎖であって、該脂肪族鎖の最大で２個のメチレン単位が、−Ｏ−、−ＮＲ−、−Ｃ（Ｏ）−もしくは−Ｓ（Ｏ） _ｚ −で任意選択で置き換えられているＣ _１〜６脂肪族鎖；または酸素、窒素もしくは硫黄から選択される０〜２個のヘテロ原子を有する３〜６員の非芳香族環から独立して選択され；各Ｊ ^Ｐは、０〜３個出現するＪ ^Ｍで任意選択で置換されており；あるいは
同一原子上に２個出現するＪ ^Ｐは、それらが結合している該原子と一緒になって、酸素、窒素または硫黄から選択される０〜２個のヘテロ原子を有する３〜６員環を形成しており；あるいは
２個出現するＪ ^Ｐは、Ｑ ^３と一緒になって、６〜１０員の飽和または部分不飽和の架橋環系を形成しており；
Ｒ ^４は、Ｈ、ハロ、Ｃ _３〜４員のシクロアルキル、３〜４員のヘテロシクリルまたはＣ _１〜４脂肪族鎖であって、該脂肪族鎖の最大で２個のメチレン単位が、−Ｏ−、−ＮＲ−、−Ｃ（Ｏ）−もしくは−Ｓ（Ｏ） _ｚ −で任意選択で置き換えられているＣ _１〜４脂肪族鎖から独立して選択され；
Ｊ ^Ｍは、ハロまたはＣ _１〜６脂肪族から独立して選択され；
ｚは０、１または２であり；
Ｒは、ＨまたはＣ _１〜４脂肪族から独立して選択される］
またはその薬学的に許容される塩もしくはプロドラッグ。
（項目２）
式Ｉの化合物：

［式中、
Ｒ ^１は、Ｈ、フルオロ、クロロまたは−Ｃ（Ｊ ^１） _２ＣＮから独立して選択され；
Ｊ ^１は、ＨまたはＣ _１〜２アルキルから独立して選択され；あるいは
２個出現するＪ ^１は、それらが結合している炭素原子と一緒になって、任意選択で置換されている３〜４員の炭素環式環を形成しており；
Ｒ ^２は、Ｈ；ハロ；−ＣＮ；またはＣ _１〜６脂肪族鎖であって、該脂肪族鎖の最大で２個のメチレン単位が、−Ｏ−、−ＮＲ−、−Ｃ（Ｏ）−もしくは−Ｓ（Ｏ） _ｚで任意選択で置き換えられているＣ _１〜６脂肪族鎖から独立して選択され；各Ｒ ^２は、０〜３個出現するＲ ^２ａで任意選択で置換されており；
Ｒ ^２ａは、ハロ、Ｃ _１〜４アルキル、−ＣＮ、または酸素、窒素もしくは硫黄から選択される０〜２個のヘテロ原子を有する３〜６員の非芳香族環から独立して選択され；
Ａは、

から独立して選択され、
Ｒ ^３は、−（Ｌ） _ｎ −Ｑ ^１またはＴから独立して選択され；
ＬおよびＴは、それぞれ独立して、Ｃ _１〜１０脂肪族鎖であり、該脂肪族鎖の最大で３個のメチレン単位が、−Ｏ−、−ＮＲ−、−Ｓ（Ｏ） _ｚ −または−Ｃ（Ｏ）−で任意選択で置き換えられており；各ＬおよびＴは、独立して、０〜５個出現するＪ ^ＬＴで置換されており；
Ｊ ^ＬＴは、ハロ、−ＣＮまたはＣ _１〜４脂肪族鎖であって、該脂肪族鎖の最大で２個のメチレン単位が、−Ｏ−、−ＮＲ−、−Ｃ（Ｏ）−もしくは−Ｓ（Ｏ） _ｚ −で任意選択で置き換えられているＣ _１〜４脂肪族鎖から独立して選択され；
ｎは０または１であり；
Ｑ ^１は、酸素、窒素もしくは硫黄から選択される０〜３個のヘテロ原子を有する３〜７員の完全飽和、部分不飽和もしくは芳香族の単環式環；または酸素、窒素もしくは硫黄から選択される０〜５個のヘテロ原子を有する７〜１２員の完全飽和、部分不飽和もしくは芳香族の二環式環から独立して選択され；Ｑ ^１は、０〜５個出現するＪ ^Ｑで独立して置換されており；
Ｊ ^Ｑは、ハロ；−ＣＮ；＝Ｏ；Ｑ ^２；またはＣ _１〜８脂肪族鎖であって、該脂肪族鎖の最大で３個のメチレン単位が、−Ｏ−、−ＮＲ−、−Ｃ（Ｏ）−もしくは−Ｓ（Ｏ） _ｚ −で任意選択で置き換えられているＣ _１〜８脂肪族鎖から独立して選択され；各々の出現するＪ ^Ｑは、０〜３個出現するＪ ^Ｒにより任意選択で置換されており；あるいは
同一原子上に２個出現するＪ ^Ｑは、それらが結合している該原子と一緒になって、酸素、窒素または硫黄から選択される０〜２個のヘテロ原子を有する３〜６員環を形成しており；２個出現するＪ ^Ｑにより形成された該環は、０〜３個出現するＪ ^Ｘで任意選択で置換されており；あるいは
２個出現するＪ ^Ｑは、Ｑ ^１と一緒になって、６〜１０員の飽和または部分不飽和の架橋環系を形成しており；
Ｑ ^２は、独立して、酸素、窒素もしくは硫黄から選択される０〜３個のヘテロ原子を有する３〜７員の完全飽和、部分不飽和もしくは芳香族の単環式環；または酸素、窒素もしくは硫黄から選択される０〜５個のヘテロ原子を有する７〜１２員の完全飽和、部分不飽和もしくは芳香族の二環式環であり；
Ｊ ^Ｒは、ハロ；−ＣＮ；＝Ｏ；→Ｏ；Ｑ ^３；またはＣ _１〜６脂肪族鎖であって、該脂肪族鎖の最大で２個のメチレン単位が、−Ｏ−、−ＮＲ−、−Ｃ（Ｏ）−もしくは−Ｓ（Ｏ） _ｚ −で任意選択で置き換えられているＣ _１〜６脂肪族鎖から独立して選択され；各Ｊ ^Ｒは、０〜３個出現するＪ ^Ｐで任意選択で置換されており；あるいは
同一原子上に２個出現するＪ ^Ｒは、それらが結合している該原子と一緒になって、酸素、窒素または硫黄から選択される０〜２個のヘテロ原子を有する３〜６員環を形成しており；２個出現するＪ ^Ｒにより形成された該環は、０〜３個出現するＪ ^Ｘで任意選択で置換されており；あるいは
２個出現するＪ ^Ｒは、Ｑ ^２と一緒になって、６〜１０員の飽和または部分不飽和の架橋環系を形成しており；
Ｑ ^３は、酸素、窒素または硫黄から選択される０〜３個のヘテロ原子を有する３〜７員の完全飽和、部分不飽和または芳香族の単環式環；酸素、窒素または硫黄から選択される０〜５個のヘテロ原子を有する７〜１２員の完全飽和、部分不飽和または芳香族の二環式環であり；
Ｊ ^Ｘは、ハロまたはＣ _１〜４脂肪族鎖であって、該脂肪族鎖の最大で２個のメチレン単位が、−Ｏ−、−ＮＲ−、−Ｃ（Ｏ）−もしくは−Ｓ（Ｏ） _ｚ −で任意選択で置き換えられているＣ _１〜４脂肪族鎖から独立して選択され；あるいは
Ｊ ^Ｐは、ハロ；−ＣＮ；＝Ｏ；Ｃ _１〜６脂肪族鎖であって、該脂肪族鎖の最大で２個のメチレン単位が、−Ｏ−、−ＮＲ−、−Ｃ（Ｏ）−もしくは−Ｓ（Ｏ） _ｚ −で任意選択で置き換えられているＣ _１〜６脂肪族鎖；または酸素、窒素もしくは硫黄から選択される０〜２個のヘテロ原子を有する３〜６員の非芳香族環から独立して選択され；あるいは
同一原子上に２個出現するＪ ^Ｐは、それらが結合している該原子と一緒になって、酸素、窒素または硫黄から選択される０〜２個のヘテロ原子を有する３〜６員環を形成しており；あるいは
２個出現するＪ ^Ｐは、Ｑ ^３と一緒になって、６〜１０員の飽和または部分不飽和の架橋環系を形成しており；
Ｒ ^４は、ＨまたはＣ _１〜３脂肪族から独立して選択され；
ｚは０、１または２であり；
Ｒは、ＨまたはＣ _１〜４脂肪族から独立して選択される］
またはその薬学的に許容される塩もしくはプロドラッグ。
（項目３）
Ｒ ^１がフルオロである、項目１または２のいずれか一項に記載の化合物。
（項目４）
Ｒ ^１が、−ＣＨ _２ＣＮまたは−ＣＨ（Ｃ _１〜２アルキル）ＣＮである、項目１または２のいずれか一項に記載の化合物。
（項目５）
Ｒ ^１がクロロである、項目１または２のいずれか一項に記載の化合物。
（項目６）
Ｒ ^１がＨである、項目１または２のいずれか一項に記載の化合物。
（項目７）
Ｒ ^２が−ＣＦ _３である、項目６に記載の化合物。
（項目８）
Ｒ ^２が、最大で２個のメチレン単位が−Ｏ−、−ＮＲ−、−Ｃ（Ｏ）−またはＳで任意選択で置き換えられているＣ _１〜６脂肪族である、項目６に記載の化合物。
（項目９）
Ｒ ^２が、−Ｏ（Ｃ _１〜３アルキル）Ｎ（Ｃ _１〜３アルキル）または−ＮＲ（Ｃ _１〜３アルキル）Ｎ（Ｃ _１〜３アルキル）である、項目８に記載の化合物。
（項目１０）
Ｒ ^２がＨである、項目１〜６のいずれか一項に記載の化合物。
（項目１１）
環Ａが

である、項目１〜６のいずれか一項に記載の化合物。
（項目１２）
環Ａが

である、項目１〜６のいずれか一項に記載の化合物。
（項目１３）
環Ａが

である、項目１〜６のいずれか一項に記載の化合物。
（項目１４）
Ｒ ^３が−（Ｌ） _ｎ −Ｑ ^１である、項目１１〜１３のいずれか一項に記載の化合物。
（項目１５）
ｎが１である、項目１４に記載の化合物。
（項目１６）
Ｌが−Ｏ−である、項目１５に記載の化合物。
（項目１７）
ｎが０である、項目１４に記載の化合物。
（項目１８）
Ｑ ^１が、酸素、窒素または硫黄から選択される０〜３個のヘテロ原子を有する３〜７員の完全飽和、部分不飽和または芳香族の単環式環から独立に選択される、項目１４〜１７のいずれか一項に記載の化合物。
（項目１９）
Ｑ ^１が３〜７員のヘテロシクリルまたはカルボシクリルである、項目１８に記載の化合物。
（項目２０）
Ｑ ^１がシクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、ピロリジニル、ピペリジニル、アゼパニル、ピラゾリジニル、イソオキサゾリジニル、オキサゾリジニル、チアゾリジニル、イミダゾリジニル、ピペラジニル、モルホリニル、チオモルホリニル、１，３−オキサジナニル、１，３−チアジナニル、ジヒドロピリジニル、ジヒドロイミダゾリル、１，３−テトラヒドロピリミジニル、ジヒドロピリミジニル、１，４−ジアゼパニル、１，４−オキサゼパニル、１，４−チアゼパニル、およびアゼチジニルから独立に選択される、項目１９に記載の化合物。
（項目２１）
Ｑ ^１が、ピロリジニル、シクロプロピル、シクロヘキシル、ピペリジニルまたはピペラジニルから独立に選択される、項目２０に記載の化合物。
（項目２２）
Ｑ ^１が５〜６員のアリールまたはヘテロアリールである、項目１８に記載の化合物。
（項目２３）
Ｑ ^１が、フェニル、ピリジニル、ピラジニル、ピリミジニル、テトラヒドロピリジニル、ピロリル、イミダゾリル、ピラゾリル、１，２，３−トリアゾリルまたは１，２，４−トリアゾリルから独立に選択される、項目２２に記載の化合物。
（項目２４）
Ｑ ^１がピリジニルである、項目２３に記載の化合物。
（項目２５）
Ｑ ^１が、酸素、窒素または硫黄から選択される１〜５個のヘテロ原子を有する７〜１２員の完全飽和、部分不飽和または芳香族の二環式環である、項目１４〜１７に記載の化合物。
（項目２６）
Ｑ ^１が、オクタヒドロピロロ［１，２−ａ］ピラジニル、５，６，７，８−テトラヒドロイミダゾ［１，２−ａ］ピリジニル、オクタヒドロ−１Ｈ−ピラジノ［１，２−ａ］ピラジニル、５，６，７，８−テトラヒドロイミダゾ［１，５−ａ］ピラジニル、２，５−ジアザビシクロ［４．１．０］ヘプタンまたはオクタヒドロピラジノ［２，１−ｃ］［１，４］オキサジニルから独立に選択される、項目２５に記載の化合物。
（項目２７）
Ｊ ^ＱがＣ _１〜６脂肪族鎖であり、該脂肪族鎖の最大で３個のメチレン単位が−Ｏ−、−ＮＲ−または−Ｃ（Ｏ）−で任意選択で置き換えられている、項目１４〜２６のいずれか一項に記載の化合物。
（項目２８）
Ｊ ^Ｑが、−Ｃ（Ｏ）−、Ｃ _１〜４アルキル、−（Ｃ _０〜４アルキル）ＮＨ _２、−（Ｃ _０〜４アルキル）ＮＨ（Ｃ _１〜４アルキル）、−（Ｃ _０〜４アルキル）Ｎ（Ｃ _１〜４アルキル） _２、−（Ｃ _０〜４アルキル）ＯＨ、−（Ｃ _０〜４アルキル）Ｏ（Ｃ _１〜４アルキル）、−Ｃ（Ｏ）ＯＨ、−Ｃ（Ｏ）Ｏ（Ｃ _１〜４アルキル）、Ｎ（Ｃ _１〜４アルキル） _２、−Ｃ（Ｏ）Ｎ（Ｃ _１〜４アルキル） _２または−（Ｃ _１〜３アルキル）Ｏ（Ｃ _１〜２アルキル）Ｎ（Ｃ _１〜３アルキル） _２から独立に選択される、項目２７に記載の化合物。
（項目２９）
Ｊ ^Ｑが、−Ｃ（Ｏ）−、Ｃ _１〜４アルキルまたは−（Ｃ _０〜４アルキル）ＮＨ _２から独立に選択される、項目２８に記載の化合物。
（項目３０）
Ｊ ^ＱがＱ ^２である、項目１４〜２６のいずれか一項に記載の化合物。
（項目３１）
Ｑ ^２が、酸素、硫黄または窒素から選択される０〜３個のヘテロ原子を有する３〜７員の完全飽和、部分不飽和または芳香族の単環式環である、項目３０に記載の化合物。
（項目３２）
Ｑ ^２が、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、オキセタニル、テトラヒドロピラニル、テトラヒドロフラニル、アゼチジニル、ピロリジニル、ピペリジニル、ピペラジニル、チオモルホリニルまたはモルホリニルから独立に選択される、項目３１に記載の化合物。
（項目３３）
Ｑ ^２がオキセタニル、ピロリジニル、テトラヒドロフラニルまたはテトラヒドロピラニルである、項目３２に記載の化合物。
（項目３４）
Ｑ ^２が、酸素、窒素または硫黄から選択される０〜５個のヘテロ原子を有する７〜１２員の完全飽和、部分不飽和または芳香族の二環式環である、項目３０に記載の化合物。
（項目３５）
Ｑ ^２が、５，６，７，８−テトラヒドロイミダゾ［１，５−ａ］ピラジニルまたは５，６，７，８−テトラヒドロイミダゾ［１，２−ａ］ピラジニルから独立に選択される、項目３４に記載の化合物。
（項目３６）
２個出現するＪ ^Ｑが、Ｑ ^１と一緒になって架橋環系を形成している、項目１９〜２１のいずれか一項に記載の化合物。
（項目３７）
Ｊ ^Ｑが＝Ｏ、ハロまたは→Ｏである、項目１９〜２１のいずれか一項に記載の化合物。
（項目３８）
同じ原子上に２個出現するＪ ^Ｑが、それらが結合している原子と一緒になって、酸素、窒素または硫黄から選択される０〜２個のヘテロ原子を有する３〜６員非芳香族環を形成している、項目１９〜２１のいずれか一項に記載の化合物。
（項目３９）
同じ原子上に２個出現するＪ ^Ｑによって、それらが結合している原子と一緒になって形成された環が、オキセタニル、シクロブチルまたはアゼチジニルから選択される、項目３８に記載の化合物。
（項目４０）
Ｊ ^Ｒが、酸素、窒素または硫黄から選択される１〜３個のヘテロ原子を有する３〜６員ヘテロシクリルである、項目２７〜３５のいずれか一項に記載の化合物。
（項目４１）
Ｊ ^Ｒが、オキセタニル、ピペリジニル、アゼチジニル、ピペラジニル、ピロリジニル、１，４−ジアゼパニルまたはモルホリニルから独立に選択される、項目４０に記載の化合物。
（項目４２）
Ｊ ^Ｒがピペラジニルである、項目４１に記載の化合物。
（項目４３）
Ｊ ^Ｒが、ハロ、＝Ｏ、−ＯＨ、Ｃ _１〜４アルキル、−（Ｃ _０〜４アルキル）Ｎ（Ｃ _１〜４アルキル） _２または−（Ｃ _０〜４アルキル）Ｏ（Ｃ _１〜４アルキル）から独立に選択される、項目２７〜３５のいずれか一項に記載の化合物。
（項目４４）
同じ原子上に２個出現するＪ ^Ｒが、それらが結合している原子と一緒になって、酸素、窒素または硫黄から選択される０〜２個のヘテロ原子を有する３〜６員芳香族または非芳香族環を形成している、項目２７〜３５のいずれか一項に記載の化合物。
（項目４５）
Ｊ ^Ｐが、ハロ、−Ｃ _１〜４アルキル、または３〜６員の非芳香族環であって、酸素、窒素もしくは硫黄から選択される０〜２個のヘテロ原子を有する非芳香族環である、項目４０〜４４のいずれか一項に記載の化合物。
（項目４６）
Ｊ ^Ｐが、ピロリジニルまたはオキセタニルから選択される、項目４５に記載の化合物。
（項目４７）
Ｒ ^３がＴである、項目１１〜１３のいずれか一項に記載の化合物。
（項目４８）
Ｔが、−（Ｃ _１〜４アルキル）、−（Ｃ _１〜４アルキル）Ｎ（Ｃ _１〜４アルキル） _２、−（Ｃ _１〜３アルキル）Ｏ（Ｃ _１〜２アルキル）Ｎ（Ｃ _１〜３アルキル） _２、−（Ｃ _１〜４アルキル）ＯＨ、−（Ｃ _１〜４アルキル）ＮＨ _２または−（Ｃ _１〜４アルキル）Ｏ（Ｃ _１〜４アルキル）から独立して選択される、項目４７に記載の化合物。
（項目４９）
Ｊ ^ＬＴが、ハロまたはＣ _１〜３アルキルである、項目４８に記載の化合物。
（項目５０）
Ａが、

から独立して選択される、項目１に記載の化合物。
（項目５１）
ｐが０である、項目５０に記載の化合物。
（項目５２）
ｐが１である、項目５０に記載の化合物。
（項目５３）
Ｒ ^４が、Ｃ _１〜４アルキルまたはハロから独立して選択される、項目５２に記載の化合物。
（項目５４）
Ｒ ^４が、メチルまたはフルオロから独立して選択される、項目５２に記載の化合物。
（項目５５）
Ｒ ^３が−（Ｌ） _ｎ −Ｑ ^１である、項目５０〜５４のいずれか一項に記載の化合物。
（項目５６）
ｎが０である、項目５５に記載の化合物。
（項目５７）
ｎが１である、項目５５に記載の化合物。
（項目５８）
Ｌが、Ｃ _１〜４アルキルから独立して選択される、項目５７に記載の化合物。
（項目５９）
Ｑ ^１がフェニルである、項目５５〜５８のいずれか一項に記載の化合物。
（項目６０）
Ｑ ^１が、３〜６員のカルボシクリルまたは４〜６員のヘテロシクリルから独立して選択される、項目５５〜５８のいずれか一項に記載の化合物。
（項目６１）
Ｑ ^１が、シクロプロピル、モルホリニル、ピロリジニル、ピペリジニル、ピペラジニル、テトラヒドロピラン、ジヒドロピランまたはテトラヒドロピリジンから独立して選択される、項目６０に記載の化合物。
（項目６２）
Ｑ ^１が５〜６員のヘテロアリールである、項目５５〜５８のいずれか一項に記載の化合物。
（項目６３）
Ｑ ^１が、ピラゾリル、ピリジニルまたはピリミジニルから独立して選択される、項目６２に記載の化合物。
（項目６４）
Ｊ ^Ｑが、Ｃ _１〜６脂肪族鎖から独立して選択され、該脂肪族鎖の最大で３個のメチレン単位が、−Ｏ−、−ＮＲ−または−Ｃ（Ｏ）−で任意選択で置き換えられている、項目５５〜６３のいずれか一項に記載の化合物。
（項目６５）
一部の実施形態では、Ｊ ^Ｑが、−Ｃ（Ｏ）−、−Ｃ（Ｏ）Ｃ _１〜４アルキルまたはＣ _１〜４アルキルから独立して選択される、項目６４に記載の化合物。
（項目６６）
Ｊ ^Ｑがメチルである、項目６５に記載の化合物。
（項目６７）
Ｊ ^Ｒが、ピペリジニルまたはピペラジニルから独立して選択される、項目６５に記載の化合物。
（項目６８）
Ｊ ^Ｐが、オキセタニルまたはアゼチジニルから独立して選択される、項目６７に記載の化合物。
（項目６９）
Ｒ ^３がＴである、項目５０〜５４のいずれか一項に記載の化合物。
（項目７０）
ＴがＣ _１〜６脂肪族鎖であり、該脂肪族鎖の最大で３個のメチレン単位が、−Ｏ−、−ＮＲ−または−Ｃ（Ｏ）−で任意選択で置き換えられている、項目６９に記載の化合物。
（項目７１）
Ｔが−（Ｃ _１〜３アルキル）Ｏ（Ｃ _１〜３アルキル）である、項目７０に記載の化合物。
（項目７２）

から独立して選択される、項目１〜７１のいずれか一項に記載の化合物。
（項目７３）
項目１〜７２のいずれか一項に記載の化合物および薬学的に許容される担体を含む医薬組成物。
（項目７４）
項目１〜７２のいずれか一項に記載の化合物またはその薬学的に許容される誘導体を投与する工程を含む、患者におけるがんを処置する方法。
（項目７５）
前記患者に、ＤＮＡ損傷剤から独立に選択される追加の治療剤を投与する工程をさらに含む方法であって；該追加の治療剤が処置を施す疾患に適しており；該追加の治療剤を、単一剤形として前記化合物と一緒に投与するか、または該化合物とは別個に複数剤形の一部として投与する、項目７４に記載の方法。
（項目７６）
前記ＤＮＡ損傷剤が選択された化学治療剤または放射線処置である、項目７５に記載の方法。
（項目７７）
前記ＤＮＡ損傷剤が、電離放射線、放射線作用のあるネオカルジノスタチン、白金製剤、トポＩ阻害剤、トポＩＩ阻害剤、代謝拮抗物質、アルキル化剤、スルホン酸アルキルまたは抗生物質から独立に選択される、項目７６に記載の方法。
（項目７８）
前記ＤＮＡ損傷剤が、電離放射線、白金製剤、トポＩ阻害剤、トポＩＩ阻害剤、代謝拮抗物質、アルキル化剤またはスルホン酸アルキルから独立に選択される、項目７５に記載の方法。
（項目７９）
前記ＤＮＡ損傷剤が、電離放射線、白金製剤、トポＩ阻害剤、トポＩＩ阻害剤または抗生物質から独立に選択される、項目７５に記載の方法。
（項目８０）
前記白金製剤が、シスプラチン、オキサリプラチン、カルボプラチン、ネダプラチン、ロバプラチン、トリプラチン４硝酸塩、ピコプラチン、サトラプラチン、ＰｒｏＬｉｎｄａｃおよびアロプラチンから独立に選択され；前記トポＩ阻害剤がカンプトテシン、トポテカン、イリノテカン／ＳＮ３８、ルビテカンおよびベロテカンから選択され；前記トポＩＩ阻害剤がエトポシド、ダウノルビシン、ドキソルビシン、アクラルビシン、エピルビシン、イダルビシン、アムルビシン、ピラルビシン、バルルビシン、ゾルビシンおよびテニポシドから選択され；前記代謝拮抗物質がアミノプテリン、メトトレキセート、ペメトレキセド、ラルチトレキセド、ペントスタチン、クラドリビン、クロファラビン、フルダラビン、チオグアニン、メルカプトプリン、フルオロウラシル、カペシタビン、テガフール、カルモフール、フロクスウリジン、シタラビン、ゲムシタビン、アザシチジンおよびヒドロキシウレアから選択され；前記アルキル化剤がメクロレタミン、シクロホスファミド、イホスファミド、トロホスファミド、クロラムブシル、メルファラン、プレドニムスチン、ベンダムスチン、ウラムスチン、エストラムスチン、カルムスチン、ロムスチン、セムスチン、ホテムスチン、ニムスチン、ラニムスチン、ストレプトゾシン、ブスルファン、マンノスルファン、トレオスルファン、カルボコン、チオテパ、トリアジコン、トリエチレンメラミン、プロカルバジン、ダカルバジン、テモゾロミド、アルトレタミン、ミトブロニトール、アクチノマイシン、ブレオマイシン、マイトマイシンおよびプリカマイシンから選択される、項目７６に記載の方法。
（項目８１）
前記白金製剤が、シスプラチン、オキサリプラチン、カルボプラチン、ネダプラチンまたはサトラプラチンから独立に選択され；前記トポＩ阻害剤が、カンプトテシン、トポテカン、イリノテカン／ＳＮ３８、ルビテカンから選択され；前記トポＩＩ阻害剤が、エトポシドから選択され；前記代謝拮抗物質が、メトトレキセート、ペメトレキセド、チオグアニン、フルダラビン、クラドリビン、シタラビン、ゲムシタビン、６−メルカプトプリンまたは５−フルオロウラシルから選択され；前記アルキル化剤が、ナイトロジェンマスタード、ニトロソウレア、トリアゼン、スルホン酸アルキル、プロカルバジンまたはアジリジンから選択され；前記抗生物質が、ヒドロキシウレア、アントラサイクリン、アントラセンジオンまたはストレプトミセスファミリーから選択される、項目７８に記載の方法。
（項目８２）
前記ＤＮＡ損傷剤が、白金製剤または電離放射線から独立に選択される、項目７８に記載の方法。
（項目８３）
前記代謝拮抗物質がゲムシタビンである、項目７８に記載の方法。
（項目８４）
前記ＤＮＡ損傷剤が電離放射線である、項目７８に記載の方法。
（項目８５）
前記ＤＮＡ損傷剤が、シスプラチンまたはカルボプラチンから独立に選択される白金製剤である、項目７８に記載の方法。
（項目８６）
前記ＤＮＡ損傷剤がエトポシドから選択されるトポＩＩ阻害剤である、項目７８に記載の方法。
（項目８７）
前記ＤＮＡ損傷剤が、テモゾロミドから選択されるアルキル化剤である、項目７８に記載の方法。
（項目８８）
前記ＤＮＡ損傷剤が、以下の：シスプラチン、カルボプラチン、ゲムシタビン、エトポシド、テモゾロミドまたは電離放射線の１つもしくは複数から独立に選択される、項目７８に記載の方法。
（項目８９）
前記がんが、以下のがん：口腔：頬側口腔、口唇、舌、口、咽頭；心臓：肉腫（血管肉腫、線維肉腫、横紋筋肉腫、脂肪肉腫）、粘液腫、横紋筋腫、線維腫、脂肪腫および奇形腫；肺：気管支がん（扁平細胞または類表皮、未分化小細胞、未分化大細胞、腺がん）、肺胞（細気管支）がん、気管支腺腫、肉腫、リンパ腫、軟骨性過誤腫、中皮腫；消化器：食道（扁平細胞がん、喉頭、腺がん、平滑筋肉腫、リンパ腫）、胃（癌腫、リンパ腫、平滑筋肉腫）、膵臓（導管腺がん、インスリノーマ、グルカゴン産生腫瘍、ガストリン産生腫瘍、カルチノイド腫瘍、ＶＩＰ産生腫瘍）、小腸（small bowel）または小腸（small
intestine）（腺がん、リンパ腫、カルチノイド腫瘍、カポジ肉腫、平滑筋腫、血管腫
、脂肪腫、神経線維腫、線維腫）、大腸（large bowel）または大腸（large intestine）（腺がん、管状腺腫、絨毛腺腫、過誤腫、平滑筋腫）、結腸、結腸−直腸、結腸直腸；直腸、尿生殖路：腎臓（腺がん、ウィルムス腫瘍［腎芽細胞腫］、リンパ腫）、膀胱および尿道（扁平細胞がん、移行細胞がん、腺がん）、前立腺（腺がん、肉腫）、睾丸（セミノーマ、奇形腫、胎生期がん、奇形がん、絨毛がん、肉腫、間質細胞がん、線維腫、線維腺腫、類腺腫瘍、脂肪腫）；肝臓：肝細胞腫（肝細胞がん）、胆管がん、肝芽腫、血管肉腫、肝細胞腺腫、血管腫、胆汁道；骨：骨原性肉腫（骨肉腫）、線維肉腫、悪性線維性組織球腫、軟骨肉腫、ユーイング肉腫、悪性リンパ腫（細網肉腫）、多発性骨髄腫、悪性巨細胞腫、脊索腫、オステオクロンフロマ（骨軟骨性外骨腫）、良性軟骨腫、軟骨芽細胞腫、軟骨粘液性線維腫、類骨骨腫および巨細胞腫；神経系：頭蓋（骨腫、血管腫、肉芽腫、黄色腫、変形性骨炎）、髄膜（髄膜腫、髄膜肉腫、神経膠腫症）、脳（星状細胞腫、髄芽腫、神経膠腫、上衣腫、胚細胞腫［松果体腫］、多形性膠芽腫、乏突起神経膠腫、神経鞘腫、網膜芽細胞腫、先天性腫瘍）、脊髄神経線維腫、髄膜腫、神経膠腫、肉腫）；婦人科／女性：子宮（子宮内膜がん）、子宮頸部（子宮頸がん、前腫瘍性子宮頸部異形成）、卵巣（卵巣がん［漿液性嚢胞腺がん、ムチン性嚢胞腺がん、未分類癌腫］、顆粒膜−莢膜細胞腫、セルトリ・ライディッヒ細胞腫、未分化胚細胞腫、悪性奇形腫）、陰門（扁平細胞がん、上皮内がん、腺がん、線維肉腫、黒色腫）、膣（明細胞がん、扁平細胞がん、ブドウ状肉腫（胎児性横紋筋肉腫）、ファロピウス管（癌腫）、胸部；皮膚：悪性黒色腫、基底細胞がん、扁平細胞がん、カポジ肉腫、ケラトアカントーマ、異形成性母斑、脂肪腫、脈管腫、皮膚線維腫、ケロイド、乾癬、甲状腺：乳頭状甲状腺がん、濾胞性甲状腺がん；髄様甲状腺がん、多発性内分泌腫瘍症２Ａ型、多発性内分泌腫瘍症２Ｂ型、家族性髄様甲状腺がん、褐色細胞腫、傍神経節腫；および副腎：神経芽細胞腫から選択される固形腫瘍である、項目８４〜８８のいずれか一項に記載の方法。
（項目９０）
前記がんが、肺または膵臓のがんから選択される、項目８９に記載の方法。
（項目９１）
前記がんが、肺がん、頭頸部がん、膵臓がん、胃がんまたは脳がんから選択される、項目８４〜８８のいずれか一項に記載の方法。
（項目９２）
前記がんが、非小細胞肺がん、小細胞肺がん、膵臓がん、胆道がん、頭頸部がん、膀胱がん、結腸直腸がん、神経膠芽腫、食道がん、乳がん、肝細胞がんまたは卵巣がんから選択される、項目８４〜８８のいずれか一項に記載の方法。
（項目９３）
前記追加の治療剤がゲムシタビンであり、前記がんが膵臓がんである、項目８９に記載の方法。
（項目９４）
ゲムシタビン、放射線治療またはゲムシタビンと放射線治療との両方から選択される追加の治療剤と併用して、患者に項目１〜７２のいずれか一項に記載の化合物の化合物を投与する工程を含む膵臓がんを処置する方法。
（項目９５）
患者に、項目１〜７２のいずれか一項に記載の化合物を投与することによって、化学治療または放射線治療から選択されるがん治療に対する膵臓がん細胞の感作性を増大させる方法。
（項目９６）
前記化学治療がゲムシタビンである、項目９５に記載の方法。
（項目９７）
前記がん治療がゲムシタビンである、項目９５に記載の方法。
（項目９８）
前記がん治療が放射線である、項目９５に記載の方法。
（項目９９）
前記がん治療がゲムシタビンおよび放射線である、項目９５に記載の方法。
（項目１００）
ゲムシタビン（１００ｎＭ）および／または放射線（６Ｇｙ）と併用して項目１〜７２のいずれか一項に記載の化合物を投与する工程を含む、膵臓がん細胞におけるＣｈｋ１（Ｓｅｒ３４５）のリン酸化を阻害する方法。
（項目１０１）
化学放射線治療と併用して、項目１〜７２のいずれか一項に記載の化合物を投与することによって膵臓がん細胞を化学放射線治療に対して感作させる方法。
（項目１０２）
前記化学放射線治療がゲムシタビンおよび放射線である、項目１０１に記載の方法。
（項目１０３）
放射線治療と併用して、項目１〜７２のいずれか一項に記載の化合物を投与することによって低酸素膵臓がん細胞を放射線感作性にする方法。
（項目１０４）
化学治療と併用して、項目１〜７２のいずれか一項に記載の化合物を投与することによって低酸素膵臓がん細胞を感作性にする方法。
（項目１０５）
前記がん細胞がＰＳＮ−１、ＭｉａＰａＣａ−２またはＰａｎｃＭがん細胞である、項目１０１〜１０４のいずれか一項に記載の方法。
（項目１０６）
放射線治療および／またはゲムシタビンと併用して、項目１〜７２のいずれか一項に記載の化合物を投与することによって損傷誘発性細胞周期チェックポイントを破壊する方法。
（項目１０７）
放射線治療および／またはゲムシタビンと併用して、項目１〜７２のいずれか一項に記載の化合物を投与することによって膵臓がん細胞における相同的組み換えによるＤＮＡ損傷の修復を阻害する方法。
（項目１０８）
前記化合物を患者に投与する、項目１０１〜１０７のいずれか一項に記載の方法。
（項目１０９）
前記化合物を膵臓がん細胞に投与する、項目１０１〜１０７のいずれか一項に記載の方法。
（項目１１０）
前記膵臓がん細胞が、ＰＳＮ−１、ＭｉａＰａＣａ−２またはＰａｎｃ−１から選択される膵臓細胞株から誘導される、項目１０９に記載の方法。
（項目１１１）
非小細胞肺がんを処置する方法であって、
以下の追加の治療剤：シスプラチンまたはカルボプラチン、エトポシドおよび電離放射線の１つまたは複数と併用して、患者に項目１〜７２のいずれか一項に記載の化合物を投与する工程を含む方法。
（項目１１２）
シスプラチンまたはカルボプラチン、エトポシドおよび電離放射線と併用して、患者に項目１に記載の化合物を投与する工程を含む、項目１１１に記載の方法。
（項目１１３）
患者に、項目１〜７２のいずれか一項に記載の化合物を投与する工程を含む、がん細胞における細胞死を促進する方法。
（項目１１４）
患者に、項目１〜７２のいずれか一項に記載の化合物を投与する工程を含む、ＤＮＡ損傷からの細胞修復を防止する方法。
（項目１１５）
生物学的試料におけるＡＴＲを阻害する方法であって、項目１〜７２のいずれか一項に記載の化合物を該生物学的試料と接触させるステップを含む方法。
（項目１１６）
前記生物学的試料が細胞である、項目１１５に記載の方法。
（項目１１７）
患者に、項目１〜７２のいずれか一項に記載の化合物を投与する工程を含む、細胞をＤＮＡ損傷剤に感作性にする方法。
（項目１１８）
前記細胞が、ＡＴＭシグナルカスケードに欠損を有するがん細胞である、項目７４〜１１７のいずれか一項に記載の方法。
（項目１１９）
前記欠損が、以下の：ＡＴＭ、ｐ５３、ＣＨＫ２、ＭＲＥ１１、ＲＡＤ５０、ＮＢＳ１、５３ＢＰ１、ＭＤＣ１、Ｈ２ＡＸ、ＭＣＰＨ１／ＢＲＩＴ１、ＣＴＩＰまたはＳＭＣ１の１つもしくは複数の発現または活性の変化である、項目１１８に記載の方法。
（項目１２０）
前記欠損が、以下の：ＡＴＭ、ｐ５３、ＣＨＫ２、ＭＲＥ１１、ＲＡＤ５０、ＮＢＳ１、５３ＢＰ１、ＭＤＣ１またはＨ２ＡＸの１つもしくは複数の発現または活性の変化である、項目１１８に記載の方法。
（項目１２１）
前記細胞が、ＤＮＡ損傷癌遺伝子を発現するがん細胞である、項目７４〜１１７のいずれか一項に記載の方法。
（項目１２２）
前記がん細胞が、以下の：Ｋ−Ｒａｓ、Ｎ−Ｒａｓ、Ｈ−Ｒａｓ、Ｒａｆ、Ｍｙｃ、Ｍｏｓ、Ｅ２Ｆ、Ｃｄｃ２５Ａ、ＣＤＣ４、ＣＤＫ２、サイクリンＥ、サイクリンＡおよびＲｂの１つもしくは複数の発現または活性の変化を有する、項目１２１に記載の方法。
（項目１２３）
前記がん、がん細胞または細胞が、塩基除去修復タンパク質の欠損を有する、項目７４〜１１７のいずれか一項に記載の方法。
（項目１２４）
前記塩基除去修復タンパク質が、ＵＮＧ、ＳＭＵＧ１、ＭＢＤ４、ＴＤＧ、ＯＧＧ１、ＭＹＨ、ＮＴＨ１、ＭＰＧ、ＮＥＩＬ１、ＮＥＩＬ２、ＮＥＩＬ３（ＤＮＡグリコシラーゼ）；ＡＰＥ１、ＡＰＥＸ２（ＡＰエンドヌクレアーゼ）；ＬＩＧ１、ＬＩＧ３（ＤＮＡリガーゼＩおよびＩＩＩ）；ＸＲＣＣ１（ＬＩＧ３アクセサリー）；ＰＮＫ、ＰＮＫＰ（ポリヌクレオチドキナーゼおよびホスファターゼ）；ＰＡＲＰ１、ＰＡＲＰ２（ポリ（ＡＤＰ−リボース）ポリメラーゼ）；ＰｏｌＢ、ＰｏｌＧ（ポリメラーゼ）；ＦＥＮ１（エンドヌクレアーゼ）またはアプラタキシンである、項目１２３に記載の方法。
（項目１２５）
前記塩基除去修復タンパク質がＰＡＲＰ１、ＰＡＲＰ２またはＰｏｌＢである、項目１２４に記載の方法。
（項目１２６）
前記塩基除去修復タンパク質がＰＡＲＰ１またはＰＡＲＰ２である、項目１２５に記載の方法。
（項目１２７）
前記患者に追加の治療剤を投与する工程をさらに含み、該薬剤が塩基除去修復タンパク質を阻害またはモジュレートする、項目７４〜１２６のいずれか一項に記載の方法。
（項目１２８）
前記塩基除去修復タンパク質が、ＵＮＧ、ＳＭＵＧ１、ＭＢＤ４、ＴＤＧ、ＯＧＧ１、ＭＹＨ、ＮＴＨ１、ＭＰＧ、ＮＥＩＬ１、ＮＥＩＬ２、ＮＥＩＬ３（ＤＮＡグリコシラーゼ）；ＡＰＥ１、ＡＰＥＸ２（ＡＰエンドヌクレアーゼ）；ＬＩＧ１、ＬＩＧ３（ＤＮＡリガーゼＩおよびＩＩＩ）；ＸＲＣＣ１（ＬＩＧ３アクセサリー）；ＰＮＫ、ＰＮＫＰ（ポリヌクレオチドキナーゼおよびホスファターゼ）；ＰＡＲＰ１、ＰＡＲＰ２（ポリ（ＡＤＰ−リボース）ポリメラーゼ）；ＰｏｌＢ、ＰｏｌＧ（ポリメラーゼ）；ＦＥＮ１（エンドヌクレアーゼ）またはアプラタキシンから選択される、項目１２７に記載の方法。
（項目１２９）
前記塩基除去修復タンパク質がＰＡＲＰ１、ＰＡＲＰ２またはＰｏｌＢから選択される、項目１２８に記載の方法。前記塩基除去修復タンパク質がＰＡＲＰ１またはＰＡＲＰ２から選択される、項目６８に記載の方法。
（項目１３０）
前記薬剤が、オラパリブ（ＡＺＤ２２８１またはＫＵ−００５９４３６としても公知である）、イニパリブ（ＢＳＩ−２０１またはＳＡＲ２４０５５０としても公知である）、ベリパリブ（ＡＢＴ−８８８としても公知である）、ルカパリブ（ＰＦ−０１３６７３３８としても公知である）、ＣＥＰ−９７２２、ＩＮＯ−１００１、ＭＫ−４８２７、Ｅ７０１６、ＢＭＮ６７３またはＡＺＤ２４６１から選択される、項目１２９に記載の方法。
（項目１３１）
式Ｉの化合物：

を調製するプロセスであって、式６の化合物：

を、適切な条件下で反応させてアミド結合を形成する工程を含み、式中：
ＪがＨまたはＣｌであり；
Ｒ ^１、Ｒ ^２およびＡが項目１〜７２に定義の通りであるプロセス。
（項目１３２）
式６の化合物：

を、式５の化合物：

を適切な条件下で反応させて活性化エステルを形成することによって調製するステップをさらに含む、項目１３１に記載のプロセス。
（項目１３３）
式Ｉの化合物：

を調製するプロセスであって、式５の化合物：

を、適切な条件下で反応させてアミド結合を形成する工程を含み、
式中、Ｒ ^１、Ｒ ^２およびＡが、項目１〜７２に定義の通りであるプロセス。
（項目１３４）
式５の化合物：

を、式４の化合物：

を適切な脱保護条件下で反応させることによって調製するステップをさらに含む、項目１３１〜１３３のいずれか一項に記載のプロセス。
（項目１３５）
式４の化合物：

を、式３の化合物：

を適切な縮合条件下で反応させてピリミジン環を形成することによって調製するステップをさらに含む、項目１３４に記載のプロセス。
（項目１３６）
式３の化合物：

を、式２の化合物：

を適切な縮合条件下で反応させてピラゾール環を形成することによって調製するステップをさらに含む、項目１３５に記載のプロセス。
（項目１３７）
式２の化合物：

を、式１の化合物：

を適切なアニオン縮合条件下で反応させることによって調製するステップをさらに含む、項目１３６に記載のプロセス。
（項目１３８）
式Ｉの化合物：

を調製するプロセスであって、式９の化合物：

を適切な縮合条件下で反応させてピリミジン環を形成する工程を含み、
式中、Ｒ ^１、Ｒ ^２およびＡは、項目１〜７２において定義した通りである、プロセス。
（項目１３９）
式９の化合物：

を、式８の化合物：

を適切な縮合条件下で反応させてピラゾール環を形成することによって調製するステップをさらに含む、項目１３６に記載のプロセス。
（項目１４０）
式８の化合物：

を、式７の化合物：

を適切な条件下で反応させてアミド結合を形成することによって調製するステップをさらに含む、項目１３７に記載のプロセス。 The compounds of the present invention are very potent ATR inhibitors. These compounds also show a surprising synergistic effect in combination therapy with other cancer drugs such as cisplatin and gemcitabine.
In one embodiment, for example, the following items are provided.
(Item 1)
Compounds of formula I:

[Where:
R ¹ And R ² Is H; halo; -C (J ¹ ) ₂ Selected from CN; -CN; W; or M;
J ¹ Is H or C _1-2 Independently selected from alkyl; or
2 appearing J ¹ Together with the carbon atom to which they are attached form an optionally substituted 3-4 membered carbocyclic ring;
M is a maximum of 3 methylene units, -O-, -NR-, -C (O)-or -S (O). _z C optionally replaced with- _1-8 Aliphatic, each M is 0-3 occurrences of R ^2a Optionally substituted with
R ^2a Is halo; -CF ₃ -CN; C _1-4 An aliphatic chain, wherein at most two methylene units of the aliphatic chain are —O—, —NR—, —C (O) — or —S (O); _z C optionally replaced with- _1-4 An aliphatic chain; or independently selected from a 3-6 membered non-aromatic ring having 0-2 heteroatoms selected from oxygen, nitrogen or sulfur;
W is a 3-7 membered fully saturated, partially unsaturated or aromatic monocyclic ring having 0-3 heteroatoms selected from oxygen, nitrogen or sulfur; or selected from oxygen, nitrogen or sulfur Independently selected from 7-12 membered fully saturated, partially unsaturated or aromatic bicyclic rings having 0-5 heteroatoms; W is 0-5 occurrences of J ^W Optionally substituted with
J ^W Is —CN, halo, —CF ₃ A maximum of two methylene units are —O—, —NR—, —C (O) — or —S (O); _z C optionally replaced with- _1-4 Independently selected from 3-6 membered non-aromatic rings having 0-2 heteroatoms selected from oxygen, nitrogen or sulfur;
Two J appearing on the same atom ^W Together with the atoms to which they are attached form a 3-6 membered ring having 0-2 heteroatoms selected from oxygen, nitrogen or sulfur; or
2 appearing J ^W Together with W forms a 6-10 membered saturated or partially unsaturated bridged ring system;
A is

Selected independently from;
p is 0, 1 or 2;
R ³ Is-(L) _n -Q ¹ Or selected independently from T;
L and T are each independently C _1-10 An aliphatic chain, wherein at most 3 methylene units of the aliphatic chain are —O—, —NR—, —S (O) _z Optionally substituted with-or -C (O)-; each L and T is 0-5 occurrences of J ^LT Independently substituted with;
J ^LT Is halo, -CN or C _1-4 An aliphatic chain, wherein at most two methylene units of the aliphatic chain are —O—, —NR—, —C (O) — or —S (O); _z C optionally replaced with- _1-4 Selected independently from the aliphatic chain;
n is 0 or 1;
Q ¹ Is a 3-7 membered fully saturated, partially unsaturated or aromatic monocyclic ring having 0-3 heteroatoms selected from oxygen, nitrogen or sulfur; or selected from oxygen, nitrogen or sulfur Independently selected from 7-12 membered fully saturated, partially unsaturated or aromatic bicyclic rings having 0-5 heteroatoms; ¹ Is J appearing 0-5 ^Q Independently substituted with
J ^Q Is halo; -CN; = O; Q ² Or C _1-8 An aliphatic chain, wherein up to three methylene units of the aliphatic chain are —O—, —NR—, —C (O) — or —S (O); _z C optionally replaced with- _1-8 Independently selected from the aliphatic chain; each occurrence of J ^Q Is J appearing 0 to 3 ^R Optionally substituted by; or
Two J appearing on the same atom ^Q Together with the atoms to which they are attached form a 3-6 membered ring having 0-2 heteroatoms selected from oxygen, nitrogen or sulfur; ^Q The ring formed by ^X Optionally substituted with; or
2 appearing J ^Q Q ¹ Together with a 6-10 membered saturated or partially unsaturated bridged ring system;
Q ² Is independently a 3-7 membered fully saturated, partially unsaturated or aromatic monocyclic ring having 0-3 heteroatoms selected from oxygen, nitrogen or sulfur; or oxygen, nitrogen or sulfur A 7-12 membered fully saturated, partially unsaturated or aromatic bicyclic ring having 0-5 heteroatoms selected from:
J ^R Is halo; —CN; ═O; → O; Q ³ Or C _1-6 An aliphatic chain, wherein at most two methylene units of the aliphatic chain are —O—, —NR—, —C (O) — or —S (O); _z C optionally replaced with- _1-6 Independently selected from the aliphatic chain; each J ^R Is J appearing 0 to 3 ^P Optionally substituted with; or
Two J appearing on the same atom ^R Together with the atoms to which they are attached form a 3-6 membered ring having 0-2 heteroatoms selected from oxygen, nitrogen or sulfur; ^R The ring formed by ^X Optionally substituted with; or
2 appearing J ^R Q ² Together with a 6-10 membered saturated or partially unsaturated bridged ring system;
Q ³ Is a 3-7 membered fully saturated, partially unsaturated or aromatic monocyclic ring having 0-3 heteroatoms selected from oxygen, nitrogen or sulfur; 0 selected from oxygen, nitrogen or sulfur A 7-12 membered fully saturated, partially unsaturated or aromatic bicyclic ring having ˜5 heteroatoms;
J ^X Is halo or C _1-4 An aliphatic chain, wherein at most two methylene units of the aliphatic chain are —O—, —NR—, —C (O) — or —S (O); _z C optionally replaced with- _1-4 Selected independently from the aliphatic chain; or
J ^P Is halo; -CN; = O; C _1-6 An aliphatic chain, wherein at most two methylene units of the aliphatic chain are —O—, —NR—, —C (O) — or —S (O); _z C optionally replaced with- _1-6 Each independently selected from an aliphatic chain; or a 3-6 membered non-aromatic ring having 0-2 heteroatoms selected from oxygen, nitrogen or sulfur; ^P Is J appearing 0 to 3 ^M Optionally substituted with; or
Two J appearing on the same atom ^P Together with the atoms to which they are attached form a 3-6 membered ring having 0-2 heteroatoms selected from oxygen, nitrogen or sulfur; or
2 appearing J ^P Q ³ Together with a 6-10 membered saturated or partially unsaturated bridged ring system;
R ⁴ H, Halo, C _3-4 Membered cycloalkyl, 3-4 membered heterocyclyl or C _1-4 An aliphatic chain, wherein at most two methylene units of the aliphatic chain are —O—, —NR—, —C (O) — or —S (O); _z C optionally replaced with- _1-4 Selected independently from the aliphatic chain;
J ^M Is halo or C _1-6 Selected independently from the aliphatic;
z is 0, 1 or 2;
R is H or C _1-4 Selected independently from aliphatics]
Or a pharmaceutically acceptable salt or prodrug thereof.
(Item 2)
Compounds of formula I:

[Where:
R ¹ H, fluoro, chloro or -C (J ¹ ) ₂ Selected independently from CN;
J ¹ Is H or C _1-2 Independently selected from alkyl; or
2 appearing J ¹ Together with the carbon atom to which they are attached form an optionally substituted 3-4 membered carbocyclic ring;
R ² Is H; halo; -CN; or C _1-6 An aliphatic chain, wherein at most two methylene units of the aliphatic chain are —O—, —NR—, —C (O) — or —S (O); _z Optionally replaced with C _1-6 Independently selected from aliphatic chains; each R ² 0 to 3 occurrences of R ^2a Optionally substituted with
R ^2a Halo, C _1-4 Independently selected from alkyl, -CN, or a 3-6 membered non-aromatic ring having 0-2 heteroatoms selected from oxygen, nitrogen or sulfur;
A is

Selected independently from
R ³ Is-(L) _n -Q ¹ Or selected independently from T;
L and T are each independently C _1-10 An aliphatic chain, wherein at most 3 methylene units of the aliphatic chain are —O—, —NR—, —S (O) _z Optionally substituted with-or -C (O)-; each L and T independently represents 0-5 occurrences of J ^LT Is replaced by;
J ^LT Is halo, -CN or C _1-4 An aliphatic chain, wherein at most two methylene units of the aliphatic chain are —O—, —NR—, —C (O) — or —S (O); _z C optionally replaced with- _1-4 Selected independently from the aliphatic chain;
n is 0 or 1;
Q ¹ Is a 3-7 membered fully saturated, partially unsaturated or aromatic monocyclic ring having 0-3 heteroatoms selected from oxygen, nitrogen or sulfur; or selected from oxygen, nitrogen or sulfur Independently selected from 7-12 membered fully saturated, partially unsaturated or aromatic bicyclic rings having 0-5 heteroatoms; ¹ Is J appearing 0-5 ^Q Independently substituted with;
J ^Q Is halo; -CN; = O; Q ² Or C _1-8 An aliphatic chain, wherein up to three methylene units of the aliphatic chain are —O—, —NR—, —C (O) — or —S (O); _z C optionally replaced with- _1-8 Independently selected from the aliphatic chain; each occurrence of J ^Q Is J appearing 0 to 3 ^R Optionally substituted by; or
Two J appearing on the same atom ^Q Together with the atoms to which they are attached form a 3-6 membered ring having 0-2 heteroatoms selected from oxygen, nitrogen or sulfur; ^Q The ring formed by ^X Optionally substituted with; or
2 appearing J ^Q Q ¹ Together with a 6-10 membered saturated or partially unsaturated bridged ring system;
Q ² Is independently a 3-7 membered fully saturated, partially unsaturated or aromatic monocyclic ring having 0-3 heteroatoms selected from oxygen, nitrogen or sulfur; or oxygen, nitrogen or sulfur A 7-12 membered fully saturated, partially unsaturated or aromatic bicyclic ring having 0-5 heteroatoms selected from:
J ^R Is halo; —CN; ═O; → O; Q ³ Or C _1-6 An aliphatic chain, wherein at most two methylene units of the aliphatic chain are —O—, —NR—, —C (O) — or —S (O); _z C optionally replaced with- _1-6 Independently selected from the aliphatic chain; each J ^R Is J appearing 0 to 3 ^P Optionally substituted with; or
Two J appearing on the same atom ^R Together with the atoms to which they are attached form a 3-6 membered ring having 0-2 heteroatoms selected from oxygen, nitrogen or sulfur; ^R The ring formed by ^X Optionally substituted with; or
2 appearing J ^R Q ² Together with a 6-10 membered saturated or partially unsaturated bridged ring system;
Q ³ Is a 3-7 membered fully saturated, partially unsaturated or aromatic monocyclic ring having 0-3 heteroatoms selected from oxygen, nitrogen or sulfur; 0 selected from oxygen, nitrogen or sulfur A 7-12 membered fully saturated, partially unsaturated or aromatic bicyclic ring having ˜5 heteroatoms;
J ^X Is halo or C _1-4 An aliphatic chain, wherein at most two methylene units of the aliphatic chain are —O—, —NR—, —C (O) — or —S (O); _z C optionally replaced with- _1-4 Selected independently from the aliphatic chain; or
J ^P Is halo; -CN; = O; C _1-6 An aliphatic chain, wherein at most two methylene units of the aliphatic chain are —O—, —NR—, —C (O) — or —S (O); _z C optionally replaced with- _1-6 An aliphatic chain; or independently selected from a 3-6 membered non-aromatic ring having 0-2 heteroatoms selected from oxygen, nitrogen or sulfur; or
Two J appearing on the same atom ^P Together with the atoms to which they are attached form a 3-6 membered ring having 0-2 heteroatoms selected from oxygen, nitrogen or sulfur; or
2 appearing J ^P Q ³ Together with a 6-10 membered saturated or partially unsaturated bridged ring system;
R ⁴ Is H or C _1-3 Selected independently from the aliphatic;
z is 0, 1 or 2;
R is H or C _1-4 Selected independently from aliphatics]
Or a pharmaceutically acceptable salt or prodrug thereof.
(Item 3)
R ¹ 3. A compound according to any one of items 1 or 2, wherein is fluoro.
(Item 4)
R ¹ Is -CH ₂ CN or -CH (C _1-2 3. A compound according to any one of items 1 or 2, which is alkyl) CN.
(Item 5)
R ¹ 3. The compound according to any one of items 1 or 2, wherein is chloro.
(Item 6)
R ¹ 3. The compound according to any one of items 1 or 2, wherein is H.
(Item 7)
R ² -CF ₃ 7. The compound according to item 6, wherein
(Item 8)
R ² Is optionally substituted with up to two methylene units with —O—, —NR—, —C (O) — or S _1-6 Item 7. The compound according to Item 6, which is aliphatic.
(Item 9)
R ² -O (C _1-3 Alkyl) N (C _1-3 Alkyl) or -NR (C _1-3 Alkyl) N (C _1-3 9. The compound according to item 8, which is alkyl).
(Item 10)
R ² 7. The compound according to any one of items 1 to 6, wherein is H.
(Item 11)
Ring A is

The compound according to any one of Items 1 to 6, wherein
(Item 12)
Ring A is

The compound according to any one of Items 1 to 6, wherein
(Item 13)
Ring A is

The compound according to any one of Items 1 to 6, wherein
(Item 14)
R ³ -(L) _n -Q ¹ The compound according to any one of Items 11 to 13, wherein
(Item 15)
Item 15. The compound according to Item 14, wherein n is 1.
(Item 16)
Item 16. The compound according to Item 15, wherein L is -O-.
(Item 17)
Item 15. The compound according to Item 14, wherein n is 0.
(Item 18)
Q ¹ Are independently selected from 3-7 membered fully saturated, partially unsaturated or aromatic monocyclic rings having 0-3 heteroatoms selected from oxygen, nitrogen or sulfur The compound as described in any one of these.
(Item 19)
Q ¹ 19. A compound according to item 18, wherein is a 3-7 membered heterocyclyl or carbocyclyl.
(Item 20)
Q ¹ Is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyrrolidinyl, piperidinyl, azepanyl, pyrazolidinyl, isoxazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,3-oxadinanyl, 1,3-thiadinanyl 21. Item 19 independently selected from: dihydropyridinyl, dihydroimidazolyl, 1,3-tetrahydropyrimidinyl, dihydropyrimidinyl, 1,4-diazepanyl, 1,4-oxazepanyl, 1,4-thiazepanyl, and azetidinyl. Compound.
(Item 21)
Q ¹ 21. A compound according to item 20, wherein is independently selected from pyrrolidinyl, cyclopropyl, cyclohexyl, piperidinyl or piperazinyl.
(Item 22)
Q ¹ 19. A compound according to item 18, wherein is a 5-6 membered aryl or heteroaryl.
(Item 23)
Q ¹ 23. The compound according to item 22, wherein is independently selected from phenyl, pyridinyl, pyrazinyl, pyrimidinyl, tetrahydropyridinyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl or 1,2,4-triazolyl.
(Item 24)
Q ¹ 24. The compound according to item 23, wherein is pyridinyl.
(Item 25)
Q ¹ 18. Compounds according to items 14-17, wherein is a 7-12 membered fully saturated, partially unsaturated or aromatic bicyclic ring having 1-5 heteroatoms selected from oxygen, nitrogen or sulfur .
(Item 26)
Q ¹ Are octahydropyrrolo [1,2-a] pyrazinyl, 5,6,7,8-tetrahydroimidazo [1,2-a] pyridinyl, octahydro-1H-pyrazino [1,2-a] pyrazinyl, 5,6 , 7,8-tetrahydroimidazo [1,5-a] pyrazinyl, 2,5-diazabicyclo [4.1.0] heptane or octahydropyrazino [2,1-c] [1,4] oxazinyl independently 26. The compound according to item 25, which is selected.
(Item 27)
J ^Q Is C _1-6 Any one of items 14 to 26, wherein the chain is an aliphatic chain, and up to 3 methylene units of the aliphatic chain are optionally replaced with -O-, -NR-, or -C (O)-. The compound according to item.
(Item 28)
J ^Q -C (O)-, C _1-4 Alkyl,-(C _0-4 Alkyl) NH ₂ ,-(C _0-4 Alkyl) NH (C _1-4 Alkyl),-(C _0-4 Alkyl) N (C _1-4 Alkyl) ₂ ,-(C _0-4 Alkyl) OH,-(C _0-4 Alkyl) O (C _1-4 Alkyl), -C (O) OH, -C (O) O (C _1-4 Alkyl), N (C _1-4 Alkyl) ₂ , -C (O) N (C _1-4 Alkyl) ₂ Or-(C _1-3 Alkyl) O (C _1-2 Alkyl) N (C _1-3 Alkyl) ₂ 28. A compound according to item 27, selected independently from
(Item 29)
J ^Q -C (O)-, C _1-4 Alkyl or-(C _0-4 Alkyl) NH ₂ 29. A compound according to item 28, selected independently from
(Item 30)
J ^Q Is Q ² 27. The compound according to any one of items 14 to 26, wherein
(Item 31)
Q ² 31. The compound of item 30, wherein is a 3-7 membered fully saturated, partially unsaturated or aromatic monocyclic ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen.
(Item 32)
Q ² 32. The compound according to item 31, wherein is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, thiomorpholinyl or morpholinyl.
(Item 33)
Q ² 33. A compound according to item 32, wherein is oxetanyl, pyrrolidinyl, tetrahydrofuranyl or tetrahydropyranyl.
(Item 34)
Q ² 31. The compound of item 30, wherein is a 7-12 membered fully saturated, partially unsaturated or aromatic bicyclic ring having 0-5 heteroatoms selected from oxygen, nitrogen or sulfur.
(Item 35)
Q ² 35. Item 34, wherein is independently selected from 5,6,7,8-tetrahydroimidazo [1,5-a] pyrazinyl or 5,6,7,8-tetrahydroimidazo [1,2-a] pyrazinyl. Compound.
(Item 36)
2 appearing J ^Q But Q ¹ 22. A compound according to any one of items 19 to 21 which together with the above forms a bridged ring system.
(Item 37)
J ^Q The compound according to any one of items 19 to 21, wherein is ═O, halo or → O.
(Item 38)
Two J appearing on the same atom ^Q Together with the atoms to which they are attached form a 3-6 membered non-aromatic ring having 0-2 heteroatoms selected from oxygen, nitrogen or sulfur, 21. The compound according to any one of 21.
(Item 39)
Two J appearing on the same atom ^Q 39. The compound of item 38, wherein the ring formed with the atoms to which they are attached is selected from oxetanyl, cyclobutyl or azetidinyl.
(Item 40)
J ^R 36. The compound according to any one of items 27 to 35, wherein is a 3 to 6 membered heterocyclyl having 1 to 3 heteroatoms selected from oxygen, nitrogen or sulfur.
(Item 41)
J ^R 41. The compound of item 40, wherein is independently selected from oxetanyl, piperidinyl, azetidinyl, piperazinyl, pyrrolidinyl, 1,4-diazepanyl or morpholinyl.
(Item 42)
J ^R 42. The compound of item 41, wherein is piperazinyl.
(Item 43)
J ^R Is halo, ═O, —OH, C _1-4 Alkyl,-(C _0-4 Alkyl) N (C _1-4 Alkyl) ₂ Or-(C _0-4 Alkyl) O (C _1-4 36. A compound according to any one of items 27 to 35, independently selected from alkyl).
(Item 44)
Two J appearing on the same atom ^R Together with the atoms to which they are attached form a 3-6 membered aromatic or non-aromatic ring having 0-2 heteroatoms selected from oxygen, nitrogen or sulfur, 36. A compound according to any one of items 27-35.
(Item 45)
J ^P Halo, -C _1-4 45. Any one of Items 40 to 44, wherein the alkyl is a 3 to 6 membered non-aromatic ring, and is a non-aromatic ring having 0 to 2 heteroatoms selected from oxygen, nitrogen or sulfur. Compound described in 1.
(Item 46)
J ^P 46. The compound of item 45, wherein is selected from pyrrolidinyl or oxetanyl.
(Item 47)
R ³ 14. The compound according to any one of items 11 to 13, wherein is T.
(Item 48)
T is-(C _1-4 Alkyl),-(C _1-4 Alkyl) N (C _1-4 Alkyl) ₂ ,-(C _1-3 Alkyl) O (C _1-2 Alkyl) N (C _1-3 Alkyl) ₂ ,-(C _1-4 Alkyl) OH,-(C _1-4 Alkyl) NH ₂ Or-(C _1-4 Alkyl) O (C _1-4 48. The compound according to item 47, which is independently selected from alkyl).
(Item 49)
J ^LT Is halo or C _1-3 49. A compound according to item 48, which is alkyl.
(Item 50)
A is

2. The compound according to item 1, which is independently selected from
(Item 51)
51. The compound according to item 50, wherein p is 0.
(Item 52)
51. The compound according to item 50, wherein p is 1.
(Item 53)
R ⁴ But C _1-4 53. A compound according to item 52, independently selected from alkyl or halo.
(Item 54)
R ⁴ 53. The compound of item 52, wherein is independently selected from methyl or fluoro.
(Item 55)
R ³ -(L) _n -Q ¹ 55. A compound according to any one of items 50 to 54, wherein
(Item 56)
56. The compound according to item 55, wherein n is 0.
(Item 57)
56. The compound according to item 55, wherein n is 1.
(Item 58)
L is C _1-4 58. The compound according to item 57, which is independently selected from alkyl.
(Item 59)
Q ¹ 59. A compound according to any one of items 55 to 58, wherein is phenyl.
(Item 60)
Q ¹ 59. The compound according to any one of items 55-58, wherein is independently selected from 3-6 membered carbocyclyl or 4-6 membered heterocyclyl.
(Item 61)
Q ¹ 61. The compound of item 60, wherein is independently selected from cyclopropyl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyran, dihydropyran or tetrahydropyridine.
(Item 62)
Q ¹ 59. A compound according to any one of items 55 to 58, wherein is a 5-6 membered heteroaryl.
(Item 63)
Q ¹ 63. The compound of item 62, wherein is independently selected from pyrazolyl, pyridinyl or pyrimidinyl.
(Item 64)
J ^Q But C _1-6 Item 55- selected independently from an aliphatic chain, wherein up to three methylene units of the aliphatic chain are optionally replaced with -O-, -NR- or -C (O)-. 64. The compound according to any one of 63.
(Item 65)
In some embodiments, J ^Q -C (O)-, -C (O) C _1-4 Alkyl or C _1-4 65. Compound according to item 64, selected independently from alkyl.
(Item 66)
J ^Q 68. The compound according to item 65, wherein is methyl.
(Item 67)
J ^R 68. The compound of item 65, wherein is independently selected from piperidinyl or piperazinyl.
(Item 68)
J ^P 68. The compound of item 67, wherein is independently selected from oxetanyl or azetidinyl.
(Item 69)
R ³ 55. A compound according to any one of items 50 to 54, wherein is T.
(Item 70)
T is C _1-6 70. The compound according to item 69, which is an aliphatic chain, wherein up to 3 methylene units of the aliphatic chain are optionally replaced with -O-, -NR- or -C (O)-.
(Item 71)
T is-(C _1-3 Alkyl) O (C _1-3 71. The compound according to item 70, which is alkyl).
(Item 72)

72. A compound according to any one of items 1 to 71, selected independently from
(Item 73)
73. A pharmaceutical composition comprising the compound according to any one of items 1 to 72 and a pharmaceutically acceptable carrier.
(Item 74)
75. A method for treating cancer in a patient, comprising administering a compound according to any one of items 1 to 72 or a pharmaceutically acceptable derivative thereof.
(Item 75)
A method further comprising administering to said patient an additional therapeutic agent independently selected from DNA damaging agents; wherein said additional therapeutic agent is suitable for the disease to be treated; 75. The method of item 74, wherein the compound is administered together with the compound as a single dosage form, or is administered separately as part of a multiple dosage form.
(Item 76)
76. The method of item 75, wherein the DNA damaging agent is a selected chemotherapeutic agent or radiation treatment.
(Item 77)
The DNA damaging agent is independently selected from ionizing radiation, radioactive neocarzinostatin, platinum preparation, topo I inhibitor, topo II inhibitor, antimetabolite, alkylating agent, alkyl sulfonate or antibiotic. The method according to item 76.
(Item 78)
76. The method of item 75, wherein the DNA damaging agent is independently selected from ionizing radiation, a platinum preparation, a topo I inhibitor, a topo II inhibitor, an antimetabolite, an alkylating agent or an alkyl sulfonate.
(Item 79)
76. The method of item 75, wherein the DNA damaging agent is independently selected from ionizing radiation, platinum preparations, topo I inhibitors, topo II inhibitors or antibiotics.
(Item 80)
The platinum preparation is independently selected from cisplatin, oxaliplatin, carboplatin, nedaplatin, lovatoplatin, triplatin tetranitrate, picoplatin, satraplatin, ProLindac and alloplatin; The topo II inhibitor is selected from etoposide, daunorubicin, doxorubicin, aclarubicin, epirubicin, idarubicin, amrubicin, pirarubicin, valrubicin, zorubicin and teniposide; Statin, cladribine, clofarabine, fludarabine, thioguanine, merca Selected from toppurin, fluorouracil, capecitabine, tegafur, carmofur, floxuridine, cytarabine, gemcitabine, azacitidine and hydroxyurea; the alkylating agent is mechloretamine, cyclophosphamide, ifosfamide, trophosphamide, chlorambucil, melphalan, prednisotin , Uramustine, estramustine, carmustine, lomustine, semustine, hotemustine, nimustine, ranimustine, streptozocin, busulfan, mannosulfan, treossulfan, carbocon, thiotepa, triadicon, triethylenemelamine, procarbazine, dacarbazine, temozolomide , Mitobronitol, actinomycin, bleomycin, my It is selected from hygromycin and plicamycin The method of claim 76.
(Item 81)
The platinum preparation is independently selected from cisplatin, oxaliplatin, carboplatin, nedaplatin or satraplatin; the topo I inhibitor is selected from camptothecin, topotecan, irinotecan / SN38, rubitecan; and the topo II inhibitor is from etoposide The antimetabolite is selected from methotrexate, pemetrexed, thioguanine, fludarabine, cladribine, cytarabine, gemcitabine, 6-mercaptopurine or 5-fluorouracil; the alkylating agent is nitrogen mustard, nitrosourea, triazene, Selected from alkyl sulfonates, procarbazine or aziridine; said antibiotic being hydroxyurea, anthracycline, anthracenedione or strepto Is selected from Seth family The method of claim 78.
(Item 82)
79. The method of item 78, wherein the DNA damaging agent is independently selected from a platinum formulation or ionizing radiation.
(Item 83)
79. A method according to item 78, wherein the antimetabolite is gemcitabine.
(Item 84)
79. A method according to item 78, wherein the DNA damaging agent is ionizing radiation.
(Item 85)
79. The method of item 78, wherein the DNA damaging agent is a platinum preparation independently selected from cisplatin or carboplatin.
(Item 86)
79. The method of item 78, wherein the DNA damaging agent is a topo II inhibitor selected from etoposide.
(Item 87)
79. A method according to item 78, wherein the DNA damaging agent is an alkylating agent selected from temozolomide.
(Item 88)
79. The method of item 78, wherein the DNA damaging agent is independently selected from one or more of the following: cisplatin, carboplatin, gemcitabine, etoposide, temozolomide or ionizing radiation.
(Item 89)
The cancer is the following cancer: oral cavity: buccal oral cavity, lip, tongue, mouth, pharynx; heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, Fibroma, lipoma and teratoma; lung: bronchial cancer (squamous or epidermis, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiole) cancer, bronchial adenoma, sarcoma, Lymphoma, cartilaginous hamartoma, mesothelioma; digestive system: esophagus (squamous cell carcinoma, larynx, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (conduit gland , Insulinoma, glucagon-producing tumor, gastrin-producing tumor, carcinoid tumor, VIP-producing tumor), small bowel or small intestine
intestine) (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma
, Lipoma, neurofibroma, fibroma), large bowel or large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colon, colon-rectum, colorectal; Rectum, urogenital tract: kidney (adenocarcinoma, Wilms tumor [nephroblastoma], lymphoma), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma) ), Testicles (seminoma, teratomas, embryonic cancer, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell cancer, fibroma, fibroadenoma, adenoid tumor, lipoma); liver: hepatocytoma ( Hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, hemangiosarcoma, hepatocellular adenoma, hemangioma, biliary tract; bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma , Ewing sarcoma, malignant lymphoma (reticulosarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteoclonfroma Osteochondral exostose), benign chondroma, chondroblastoma, chondromyoma fibromas, osteoid and giant cell tumors; nervous system: skull (osteomas, hemangiomas, granulomas, xanthomas, deformable) Osteomyelitis), meninges (meningioma, meningiosarcoma, glioma), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pineomas], many Glioblastoma, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma); gynecology / female: uterus (uterus) Endometrial cancer), cervix (cervical cancer, preneoplastic cervical dysplasia), ovary (ovarian cancer [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), Granulosa-capsular cell tumor, Sertoli Leydig cell tumor, anaplastic germoma, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina ( Clear cell carcinoma, squamous Squamous cell carcinoma, grape sarcoma (fetal rhabdomyosarcoma), fallopian tube (carcinoma), breast; skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi sarcoma, keratoacanthoma, dysplasia Nevus, lipoma, angioma, dermal fibroma, keloid, psoriasis, thyroid: papillary thyroid cancer, follicular thyroid cancer; medullary thyroid cancer, multiple endocrine neoplasia type 2A, multiple endocrine 89. Any of items 84-88, wherein the tumor is a solid tumor selected from type 2B, familial medullary thyroid cancer, pheochromocytoma, paraganglioma; and adrenal gland: neuroblastoma. Method.
(Item 90)
90. The method of item 89, wherein the cancer is selected from lung or pancreatic cancer.
(Item 91)
89. The method according to any one of items 84 to 88, wherein the cancer is selected from lung cancer, head and neck cancer, pancreatic cancer, stomach cancer or brain cancer.
(Item 92)
Non-small cell lung cancer, small cell lung cancer, pancreatic cancer, biliary tract cancer, head and neck cancer, bladder cancer, colorectal cancer, glioblastoma, esophageal cancer, breast cancer, hepatocytes The method according to any one of items 84 to 88, selected from cancer or ovarian cancer.
(Item 93)
90. The method of item 89, wherein the additional therapeutic agent is gemcitabine and the cancer is pancreatic cancer.
(Item 94)
75. A pancreas comprising administering to a patient a compound of any one of items 1 to 72 in combination with an additional therapeutic agent selected from gemcitabine, radiotherapy or both gemcitabine and radiotherapy To treat cancer.
(Item 95)
75. A method for increasing the sensitization of pancreatic cancer cells to a cancer treatment selected from chemotherapy or radiation therapy by administering to the patient a compound according to any one of items 1 to 72.
(Item 96)
96. The method of item 95, wherein the chemotherapy is gemcitabine.
(Item 97)
96. The method of item 95, wherein the cancer treatment is gemcitabine.
(Item 98)
96. The method of item 95, wherein the cancer treatment is radiation.
(Item 99)
96. The method of item 95, wherein the cancer treatment is gemcitabine and radiation.
(Item 100)
Inhibiting phosphorylation of Chk1 (Ser345) in pancreatic cancer cells, comprising administering the compound according to any one of items 1 to 72 in combination with gemcitabine (100 nM) and / or radiation (6 Gy) Method.
(Item 101)
A method for sensitizing pancreatic cancer cells to chemoradiotherapy by administering a compound according to any one of items 1 to 72 in combination with chemoradiotherapy.
(Item 102)
102. The method of item 101, wherein the chemoradiotherapy is gemcitabine and radiation.
(Item 103)
A method for rendering hypoxic pancreatic cancer cells radiation sensitizing by administering the compound according to any one of Items 1 to 72 in combination with radiation therapy.
(Item 104)
A method for sensitizing hypoxic pancreatic cancer cells by administering a compound according to any one of items 1 to 72 in combination with chemotherapy.
(Item 105)
105. The method according to any one of items 101 to 104, wherein the cancer cells are PSN-1, MiaPaCa-2 or PancM cancer cells.
(Item 106)
75. A method of destroying an injury-induced cell cycle checkpoint by administering a compound according to any one of items 1 to 72 in combination with radiation therapy and / or gemcitabine.
(Item 107)
75. A method of inhibiting the repair of DNA damage by homologous recombination in pancreatic cancer cells by administering the compound according to any one of items 1 to 72 in combination with radiation therapy and / or gemcitabine.
(Item 108)
108. The method of any one of items 101 to 107, wherein the compound is administered to a patient.
(Item 109)
108. The method according to any one of items 101 to 107, wherein the compound is administered to pancreatic cancer cells.
(Item 110)
110. The method of item 109, wherein the pancreatic cancer cells are derived from a pancreatic cell line selected from PSN-1, MiaPaCa-2 or Panc-1.
(Item 111)
A method of treating non-small cell lung cancer comprising:
75. A method comprising administering to a patient a compound according to any one of items 1 to 72 in combination with one or more of the following additional therapeutic agents: cisplatin or carboplatin, etoposide and ionizing radiation.
(Item 112)
111. The method of item 111, comprising administering to the patient the compound of item 1 in combination with cisplatin or carboplatin, etoposide and ionizing radiation.
(Item 113)
A method for promoting cell death in cancer cells, comprising a step of administering the compound according to any one of items 1 to 72 to a patient.
(Item 114)
75. A method of preventing cell repair from DNA damage comprising administering to a patient a compound according to any one of items 1 to 72.
(Item 115)
75. A method of inhibiting ATR in a biological sample, comprising contacting a compound according to any one of items 1 to 72 with the biological sample.
(Item 116)
116. The method of item 115, wherein the biological sample is a cell.
(Item 117)
75. A method of sensitizing a cell to a DNA damaging agent comprising administering to a patient a compound according to any one of items 1 to 72.
(Item 118)
118. The method according to any one of items 74 to 117, wherein the cell is a cancer cell having a defect in an ATM signal cascade.
(Item 119)
119. Item 118, wherein the deficiency is a change in the expression or activity of one or more of the following: ATM, p53, CHK2, MRE11, RAD50, NBS1, 53BP1, MDC1, H2AX, MCPH1 / BRIT1, CTIP or SMC1 the method of.
(Item 120)
119. The method of item 118, wherein the deficiency is a change in the expression or activity of one or more of the following: ATM, p53, CHK2, MRE11, RAD50, NBS1, 53BP1, MDC1 or H2AX.
(Item 121)
118. The method according to any one of items 74 to 117, wherein the cell is a cancer cell that expresses a DNA-damaged oncogene.
(Item 122)
Said cancer cell is expressed by one or more of the following: K-Ras, N-Ras, H-Ras, Raf, Myc, Mos, E2F, Cdc25A, CDC4, CDK2, cyclin E, cyclin A and Rb or 122. A method according to item 121, wherein the method has a change in activity.
(Item 123)
118. The method according to any one of items 74 to 117, wherein the cancer, cancer cell or cell has a base excision repair protein deficiency.
(Item 124)
The base excision repair protein is UNG, SMUG1, MBD4, TDG, OGG1, MYH, NTH1, MPG, NEIL1, NEIL2, NEIL3 (DNA glycosylase); APE1, APEX2 (AP endonuclease); LIG1, LIG3 (DNA ligase I and III); XRCC1 (LIG3 accessory); PNK, PNKP (polynucleotide kinase and phosphatase); PARP1, PARP2 (poly (ADP-ribose) polymerase); PolB, PolG (polymerase); FEN1 (endonuclease) or aplataxin, 124. A method according to item 123.
(Item 125)
125. A method according to item 124, wherein the base excision repair protein is PARP1, PARP2, or PolB.
(Item 126)
126. A method according to item 125, wherein the base excision repair protein is PARP1 or PARP2.
(Item 127)
127. The method of any one of items 74-126, further comprising administering an additional therapeutic agent to the patient, wherein the agent inhibits or modulates a base excision repair protein.
(Item 128)
The base excision repair protein is UNG, SMUG1, MBD4, TDG, OGG1, MYH, NTH1, MPG, NEIL1, NEIL2, NEIL3 (DNA glycosylase); APE1, APEX2 (AP endonuclease); LIG1, LIG3 (DNA ligase I and III); XRCC1 (LIG3 accessory); PNK, PNKP (polynucleotide kinase and phosphatase); PARP1, PARP2 (poly (ADP-ribose) polymerase); PolB, PolG (polymerase); FEN1 (endonuclease) or aplataxin 128. The method according to item 127.
(Item 129)
129. The method of item 128, wherein the base excision repair protein is selected from PARP1, PARP2 or PolB. 70. The method of item 68, wherein the base excision repair protein is selected from PARP1 or PARP2.
(Item 130)
The drugs include olaparib (also known as AZD2281 or KU-0059436), iniparib (also known as BSI-201 or SAR240550), veriparib (also known as ABT-888), lucaparib (as PF-01367338). 130. The method of item 129, selected from CEP-9722, INO-1001, MK-4827, E7016, BMN673 or AZD2461.
(Item 131)
Compounds of formula I:

Wherein the compound of formula 6:

Comprising reacting under appropriate conditions to form an amide bond, wherein:
J is H or Cl;
R ¹ , R ² And A is a process as defined in items 1-72.
(Item 132)
Compound of formula 6:

A compound of formula 5:

132. The process of item 131, further comprising the step of preparing by reacting under suitable conditions to form an activated ester.
(Item 133)
Compounds of formula I:

Wherein the compound of formula 5:

Reacting under appropriate conditions to form an amide bond,
Where R ¹ , R ² And A is as defined in items 1-72.
(Item 134)
Compound of formula 5:

A compound of formula 4:

134. The process according to any one of items 131-133, further comprising the step of preparing by reacting under suitable deprotection conditions.
(Item 135)
Compound of formula 4:

A compound of formula 3:

135. The process of item 134, further comprising the step of preparing by reacting under appropriate condensation conditions to form a pyrimidine ring.
(Item 136)
Compound of formula 3:

A compound of formula 2:

140. The process of item 135, further comprising the step of preparing by reacting under appropriate condensation conditions to form a pyrazole ring.
(Item 137)
Compound of formula 2:

A compound of formula 1:

138. The process of item 136, further comprising the step of preparing by reacting under suitable anionic condensation conditions.
(Item 138)
Compounds of formula I:

Wherein the compound of formula 9:

Reacting under suitable condensation conditions to form a pyrimidine ring,
Where R ¹ , R ² And A is a process as defined in items 1-72.
(Item 139)
Compound of formula 9:

A compound of formula 8:

140. The process of item 136, further comprising the step of preparing by reacting under appropriate condensation conditions to form a pyrazole ring.
(Item 140)
Compound of formula 8:

A compound of formula 7:

138. The process of item 137, further comprising the step of preparing by reacting under appropriate conditions to form an amide bond.

Claims

Compounds of formula I:

[Where:
R ¹ and R ² are independently selected from H; halo; —C (J ¹ ) ₂ CN; —CN; W; or M;
J ¹ is independently selected from H or C _1-2 alkyl; or two occurrences of J ¹ are optionally substituted together with the carbon atom to which they are attached. Forms a 4-membered carbocyclic ring;
M is a C _1-8 aliphatic in which up to 3 methylene units are optionally replaced with —O—, —NR—, —C (O) — or —S (O) _z —. Each M is optionally substituted with 0-3 occurrences of R ^2a ;
R ^2a is halo; —CF ₃ ; —CN; C _1-4 aliphatic chain, and at most two methylene units of the aliphatic chain are —O—, —NR—, —C (O )-Or -S (O) _z- , optionally substituted _C1-4 aliphatic chain; or 3-6 membered having 0-2 heteroatoms selected from oxygen, nitrogen or sulfur Independently selected from non-aromatic rings;
W is a 3-7 membered fully saturated, partially unsaturated or aromatic monocyclic ring having 0-3 heteroatoms selected from oxygen, nitrogen or sulfur; or selected from oxygen, nitrogen or sulfur Independently selected from 7-12 membered fully saturated, partially unsaturated or aromatic bicyclic rings having 0-5 heteroatoms; W is optional with 0-5 occurrences of ^JW Is replaced by;
^JW is —CN, halo, —CF ₃ ; up to two methylene units are optionally replaced with —O—, —NR—, —C (O) — or —S (O) _z —. C _{1 to 4} aliphatic there; or oxygen, is independently selected from non-aromatic ring of 3 to 6-membered having 0-2 heteroatoms selected from nitrogen or sulfur;
J ^W appearing two times on the same atom, together with the atoms to which they are bonded, form a 3-6 membered ring having 0-2 heteroatoms selected from oxygen, nitrogen or sulfur has; J ^W to or appearing two together is W, forms a bridged ring system, saturated or partially unsaturated 6-10 membered;
A is

Selected independently from;
p is 0, 1 or 2;
R ³ is independently selected from-(L) _n -Q ¹ or T;
L and T are each independently a C _1-10 aliphatic chain, wherein at most 3 methylene units of the aliphatic chain are —O—, —NR—, —S (O) _z — or -C (O) - is replaced by optionally; each L and T are independently substituted with 0-5 occurrences of ^{J LT;}
J ^LT is halo, —CN or C _1-4 aliphatic chain, wherein at most two methylene units are —O—, —NR—, —C (O) — or — Independently selected from C _1-4 aliphatic chains optionally substituted with S (O) _z —;
n is 0 or 1;
Q ¹ is a 3-7 membered fully saturated, partially unsaturated or aromatic monocyclic ring having 0-3 heteroatoms selected from oxygen, nitrogen or sulfur; or selected from oxygen, nitrogen or sulfur Independently selected from 7 to 12 membered fully saturated, partially unsaturated or aromatic bicyclic rings having 0 to 5 heteroatoms; Q ¹ is 0 to 5 occurrences of J ^Q Independently substituted;
J ^Q is halo; —CN; ═O; Q ² ; or a C _1-8 aliphatic chain, wherein up to three methylene units of the aliphatic chain are —O—, —NR—, — Independently selected from C _1-8 aliphatic chains optionally substituted with C (O) — or —S (O) _z —; each occurrence of J ^Q is 0-3 occurrences of J It is is optionally substituted with ^R; J ^Q is the two appearing on or the same atoms, 0-2 of which together with the atom to which they are attached are selected from oxygen, nitrogen or sulfur of it forms a 3-6 membered ring having a hetero atom; two said ring formed by J ^Q appearing is optionally is substituted by at J ^X appearing 0-3; or two Appearing J ^Q together with Q ¹ forms a 6-10 membered saturated or partially unsaturated bridged ring system. And;
Q ² is independently a 3-7 membered fully saturated, partially unsaturated or aromatic monocyclic ring having 0-3 heteroatoms selected from oxygen, nitrogen or sulfur; or oxygen, nitrogen Or a 7-12 membered fully saturated, partially unsaturated or aromatic bicyclic ring having 0-5 heteroatoms selected from sulfur;
^JR is halo; —CN; ═O; → O; Q ³ ; or C _1-6 aliphatic chain, wherein at most two methylene units of the aliphatic chain are —O—, —NR Independently selected from _C1-6 aliphatic chains optionally substituted with-, -C (O)-or -S (O) _z- ; each ^JR represents 0-3 occurrences of J Optionally substituted with ^P ; or two occurrences of ^JR on the same atom, together with the atoms to which they are attached, 0-2 selected from oxygen, nitrogen or sulfur of it forms a 3-6 membered ring having a hetero atom; two said ring formed by J ^R of occurrence is optionally is substituted by at J ^X appearing 0-3; or two emerging J ^R, together with Q ^2, forms a saturated or partially unsaturated bridged ring system of 6-10 members;
Q ³ is a 3-7 membered fully saturated, partially unsaturated or aromatic monocyclic ring having 0-3 heteroatoms selected from oxygen, nitrogen or sulfur; selected from oxygen, nitrogen or sulfur A 7-12 membered fully saturated, partially unsaturated or aromatic bicyclic ring having 0-5 heteroatoms;
J ^X is halo or a C _1-4 aliphatic chain, wherein up to two methylene units of the aliphatic chain are —O—, —NR—, —C (O) — or —S (O ) _z - optionally independently from _{C 1 to 4} aliphatic chain are replaced are selected; or J ^P is halo; -CN; = _O; a _{C 1 to 6} aliphatic chain, wherein C _1-6 aliphatic chain wherein up to two methylene units of the aliphatic chain are optionally replaced by —O—, —NR—, —C (O) — or —S (O) _z —. ; or oxygen, nitrogen or 0-2 independently from the non-aromatic ring of 3 to 6-membered having hetero atoms selected from nitrogen selected; each J ^P is a J ^M appearing 0-3 optionally it is substituted with; 2 J ^P is appearing on or the same atom, taken together with the atom to which they are attached Oxygen, forms a 3-6 membered ring having 0-2 heteroatoms selected from nitrogen or sulfur; or two occurrences of ^{J P,} together with ^{Q 3,} 6 to 10-membered Forming a saturated or partially unsaturated bridged ring system of
R ⁴ is H, halo, C _3-4 membered cycloalkyl, 3-4 membered heterocyclyl or C _1-4 aliphatic chain, wherein at most 2 methylene units of the aliphatic chain are — Independently selected from C _1-4 aliphatic chains optionally substituted with O—, —NR—, —C (O) — or —S (O) _z —;
J ^M is independently selected from halo or C _1-6 aliphatic;
z is 0, 1 or 2;
R is independently selected from H or C _1-4 aliphatic]
Or a pharmaceutically acceptable salt or prodrug thereof.

Compounds of formula I:

[Where:
R ¹ is independently selected from H, fluoro, chloro or —C (J ¹ ) ₂ CN;
J ¹ is independently selected from H or C _1-2 alkyl; or two occurrences of J ¹ are optionally substituted together with the carbon atom to which they are attached. Forms a 4-membered carbocyclic ring;
R ² is H; halo; —CN; or C _1-6 aliphatic chain wherein at most two methylene units are —O—, —NR—, —C (O) - or -S _{(O) z} independently from _{C 1 to 6} aliphatic chain has been replaced with optionally selected in; each ^{R 2} is optionally substituted with ^{R 2a} appearing 0-3 There;
R ^2a is independently selected from halo, C _1-4 alkyl, —CN, or a 3-6 membered non-aromatic ring having 0-2 heteroatoms selected from oxygen, nitrogen or sulfur;
A is

Selected independently from
R ³ is independently selected from-(L) _n -Q ¹ or T;
L and T are each independently a C _1-10 aliphatic chain, wherein at most 3 methylene units of the aliphatic chain are —O—, —NR—, —S (O) _z — or -C (O) - is replaced by optionally; each L and T are independently is substituted with 0-5 occurrences of ^{J LT;}
J ^LT is halo, —CN or C _1-4 aliphatic chain, wherein at most two methylene units are —O—, —NR—, —C (O) — or — Independently selected from C _1-4 aliphatic chains optionally substituted with S (O) _z —;
n is 0 or 1;
Q ¹ is a 3-7 membered fully saturated, partially unsaturated or aromatic monocyclic ring having 0-3 heteroatoms selected from oxygen, nitrogen or sulfur; or selected from oxygen, nitrogen or sulfur Independently selected from 7 to 12 membered fully saturated, partially unsaturated or aromatic bicyclic rings having 0 to 5 heteroatoms; Q ¹ is 0 to 5 occurrences of J ^Q Independently substituted;
J ^Q is halo; —CN; ═O; Q ² ; or a C _1-8 aliphatic chain, wherein up to three methylene units of the aliphatic chain are —O—, —NR—, — Independently selected from C _1-8 aliphatic chains optionally substituted with C (O) — or —S (O) _z —; each occurrence of J ^Q is 0-3 occurrences of J It is is optionally substituted with ^R; J ^Q is the two appearing on or the same atoms, 0-2 of which together with the atom to which they are attached are selected from oxygen, nitrogen or sulfur of it forms a 3-6 membered ring having a hetero atom; two said ring formed by J ^Q appearing is optionally is substituted by at J ^X appearing 0-3; or two Appearing J ^Q together with Q ¹ forms a 6-10 membered saturated or partially unsaturated bridged ring system. And;
Q ² is independently a 3-7 membered fully saturated, partially unsaturated or aromatic monocyclic ring having 0-3 heteroatoms selected from oxygen, nitrogen or sulfur; or oxygen, nitrogen Or a 7-12 membered fully saturated, partially unsaturated or aromatic bicyclic ring having 0-5 heteroatoms selected from sulfur;
^JR is halo; —CN; ═O; → O; Q ³ ; or C _1-6 aliphatic chain, wherein at most two methylene units of the aliphatic chain are —O—, —NR Independently selected from _C1-6 aliphatic chains optionally substituted with-, -C (O)-or -S (O) _z- ; each ^JR represents 0-3 occurrences of J Optionally substituted with ^P ; or two occurrences of ^JR on the same atom, together with the atoms to which they are attached, 0-2 selected from oxygen, nitrogen or sulfur of it forms a 3-6 membered ring having a hetero atom; two said ring formed by J ^R of occurrence is optionally is substituted by at J ^X appearing 0-3; or two emerging J ^R, together with Q ^2, forms a saturated or partially unsaturated bridged ring system of 6-10 members;
Q ³ is a 3-7 membered fully saturated, partially unsaturated or aromatic monocyclic ring having 0-3 heteroatoms selected from oxygen, nitrogen or sulfur; selected from oxygen, nitrogen or sulfur A 7-12 membered fully saturated, partially unsaturated or aromatic bicyclic ring having 0-5 heteroatoms;
J ^X is halo or a C _1-4 aliphatic chain, wherein up to two methylene units of the aliphatic chain are —O—, —NR—, —C (O) — or —S (O ) _z - optionally independently from _{C 1 to 4} aliphatic chain are replaced are selected; or J ^P is halo; -CN; = _O; a _{C 1 to 6} aliphatic chain, wherein C _1-6 aliphatic chain wherein up to two methylene units of the aliphatic chain are optionally replaced by —O—, —NR—, —C (O) — or —S (O) _z —. ; or oxygen, nitrogen or 0-2 independently from the non-aromatic ring of 3 to 6-membered having hetero atoms selected from sulfur is selected; or J ^P of two appearing on the same atom, they With 0 to 2 heteroatoms selected from oxygen, nitrogen or sulfur together with the atoms to which To form a 3-6 membered ring and that; J ^P to or appearing two together with Q ^3, forms a bridged ring system, saturated or partially unsaturated 6-10 membered;
R ⁴ is independently selected from H or C _1-3 aliphatic;
z is 0, 1 or 2;
R is independently selected from H or C _1-4 aliphatic]
Or a pharmaceutically acceptable salt or prodrug thereof.

The compound according to any one of claims 1 and 2, or a pharmaceutically acceptable salt or prodrug thereof, wherein R ¹ is fluoro.

R ¹ is _-CH 2 CN or -CH _{(C 1 to 2} alkyl) CN, A compound according to any one of claims 1 or 2, or a pharmaceutically acceptable salt or prodrug thereof.

The compound according to any one of claims 1 and 2, or a pharmaceutically acceptable salt or prodrug thereof, wherein R ¹ is chloro.

The compound according to any one of claims 1 and 2, or a pharmaceutically acceptable salt or prodrug thereof, wherein R ¹ is H.

R ² is -CF _3, a compound or a pharmaceutically acceptable salt or prodrug according to claim 6.

7. R ² is C _1-6 aliphatic wherein up to two methylene units are optionally replaced with —O—, —NR—, —C (O) — or S. Or a pharmaceutically acceptable salt or prodrug thereof .

R ² is -O _{(C 1 to 3} alkyl) _{N (C 1 to 3} alkyl) or -NR _{(C 1 to 3} alkyl) _{N (C 1 to 3} alkyl), A compound according to claim 8 or A pharmaceutically acceptable salt or prodrug thereof .

The compound according to any one of claims 1 to 6, wherein R ² is H, or a pharmaceutically acceptable salt or prodrug thereof .

Ring A is

The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or prodrug thereof .

Ring A is

R ³ is - _(L) is a n -Q ^1, compound, or a pharmaceutically acceptable salt or prodrug according to any one of claims 11 to 13.

15. The compound according to claim 14, wherein n is 1, or a pharmaceutically acceptable salt or prodrug thereof .

16. The compound according to claim 15, wherein L is -O-, or a pharmaceutically acceptable salt or prodrug thereof .

15. The compound according to claim 14, wherein n is 0, or a pharmaceutically acceptable salt or prodrug thereof .

Q ¹ is independently selected from 3 to 7 membered fully saturated, partially unsaturated or aromatic monocyclic rings having 0 to 3 heteroatoms selected from oxygen, nitrogen or sulfur. The compound according to any one of 14 to 17, or a pharmaceutically acceptable salt or prodrug thereof .

Q ¹ is a 3-7 membered heterocyclyl or carbocyclyl, compounds or a pharmaceutically acceptable salt or prodrug of claim 18.

Q ¹ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyrrolidinyl, piperidinyl, azepanyl, pyrazolidinyl, isoxazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,3-oxazinanyl, 1,3 -Independently selected from thiadinanyl, dihydropyridinyl, dihydroimidazolyl, 1,3-tetrahydropyrimidinyl, dihydropyrimidinyl, 1,4-diazepanyl, 1,4-oxazepanyl, 1,4-thiazepanyl, and azetidinyl. 19. The compound according to 19, or a pharmaceutically acceptable salt or prodrug thereof .

21. A compound according to claim 20, or a pharmaceutically acceptable salt or prodrug thereof , wherein Q < ¹ > is independently selected from pyrrolidinyl, cyclopropyl, cyclohexyl, piperidinyl or piperazinyl.

19. A compound according to claim 18 or a pharmaceutically acceptable salt or prodrug thereof, wherein Q < ¹ > is 5-6 membered aryl or heteroaryl.

Q ¹ is phenyl, pyridinyl, pyrazinyl, pyrimidinyl, tetrahydropyridinyl, pyrrolyl, imidazolyl, pyrazolyl, independently selected from 1,2,3-triazolyl or 1,2,4-triazolyl, claim 22 Or a pharmaceutically acceptable salt or prodrug thereof .

Q ¹ is pyridinyl, the compound or a pharmaceutically acceptable salt or prodrug of claim 23.

Q ¹⁴ is a 7-12 membered fully saturated, partially unsaturated or aromatic bicyclic ring having 1-5 heteroatoms selected from oxygen, nitrogen or sulfur Or a pharmaceutically acceptable salt or prodrug thereof .

Q ¹ is octahydropyrrolo [1,2-a] pyrazinyl, 5,6,7,8-tetrahydroimidazo [1,2-a] pyridinyl, octahydro-1H-pyrazino [1,2-a] pyrazinyl, 5 , 6,7,8-tetrahydroimidazo [1,5-a] pyrazinyl, 2,5-diazabicyclo [4.1.0] heptane or octahydropyrazino [2,1-c] [1,4] oxazinyl 26. The compound of claim 25, or a pharmaceutically acceptable salt or prodrug thereof , which is independently selected.

J ^Q is a C _1-6 aliphatic chain, wherein up to 3 methylene units of the aliphatic chain are optionally replaced with —O—, —NR— or —C (O) —. Item 27. The compound according to any one of Items 14 to 26, or a pharmaceutically acceptable salt or prodrug thereof .

J ^Q is —C (O) —, C _1-4 alkyl, — (C _0-4 alkyl) NH ₂ , — (C _0-4 alkyl) NH (C _1-4 alkyl), — (C _{0-0 4} alkyl) _{N (C 1 to 4} _alkyl) _2, - _(C _0~4 alkyl) _OH, - _(C 0~4 alkyl) _{O (C 1 to 4} alkyl), - C (O) OH , -C ( O) _{O (C 1 to 4} alkyl), _{N (C 1 to 4} _{_{alkyl) 2, -C (O) N}} (C 1~4 _{alkyl) 2} or - _{(C 1 to 3} alkyl) _{O (C 1 to 2} 28. A compound according to claim 27 or a pharmaceutically acceptable salt or prodrug thereof , independently selected from alkyl) N ( _C1-3alkyl ) ₂ .

J ^Q _{is, -C (O) -, C} 1~4 alkyl or - _{(C 0 to 4} alkyl) is selected from NH ₂ independently, a compound or a pharmaceutically acceptable salt thereof according to claim 28 Or a prodrug .

J ^Q is Q ^2, a compound or a pharmaceutically acceptable salt or prodrug according to any one of claims 14 to 26.

Q ² is oxygen, fully saturated 3- to 7-membered having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, which is partially unsaturated or aromatic monocyclic ring, according to claim 30 A compound or a pharmaceutically acceptable salt or prodrug thereof .

Q ² is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, are independently selected from thiomorpholinyl or morpholinyl, a compound or a pharmaceutically according to claim 31 Acceptable salt or prodrug .

Q ² is oxetanyl, pyrrolidinyl, tetrahydrofuranyl or tetrahydropyranyl, a compound or a pharmaceutically acceptable salt or prodrug of claim 32.

Q ² is oxygen, 7-12 membered fully saturated with 0-5 heteroatoms selected from nitrogen or sulfur, partially unsaturated or aromatic bicyclic ring, as set forth in claim 30 A compound or a pharmaceutically acceptable salt or prodrug thereof .

The Q ² is independently selected from 5,6,7,8-tetrahydroimidazo [1,5-a] pyrazinyl or 5,6,7,8-tetrahydroimidazo [1,2-a] pyrazinyl. 34. A compound according to 34 or a pharmaceutically acceptable salt or prodrug thereof .

Two occurrences of J ^Q, together with Q ¹ to form a bridged ring system, the compound or a pharmaceutically acceptable salt or prodrug according to any one of claims 19 to 21 .

J ^Q is = O, halo or → O, a compound or a pharmaceutically acceptable salt or prodrug according to any one of claims 19 to 21.

J ^Q of two appearing on the same atom, together with the atoms to which they are attached, 3-6 membered non-aromatic having 0-2 heteroatoms selected from oxygen, nitrogen or sulfur The compound according to any one of claims 19 to 21, or a pharmaceutically acceptable salt or prodrug thereof , which forms a ring.

By J ^Q of two appearing on the same atom, they are formed together with the atoms connecting ring, oxetanyl, is selected from cyclobutyl or azetidinyl, compound or pharmaceutically according to claim 38 Acceptable salt or prodrug .

36. The compound according to any one of claims 27 to 35, or a pharmaceutically acceptable salt thereof, wherein ^JR is a 3-6 membered heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen or sulfur. Salt or prodrug .

J ^R is, oxetanyl, piperidinyl, azetidinyl, piperazinyl, pyrrolidinyl, is independently selected from 1,4-diazepanyl, or morpholinyl, a compound or a pharmaceutically acceptable salt or prodrug of claim 40.

42. The compound of claim 41, or a pharmaceutically acceptable salt or prodrug thereof , wherein ^JR is piperazinyl.

^JR is halo, ═O, —OH, C _1-4 alkyl, — (C _0-4 alkyl) N (C _1-4 alkyl) ₂ or — (C _0-4 alkyl) O (C _1-4 36. The compound according to any one of claims 27 to 35, or a pharmaceutically acceptable salt or prodrug thereof , independently selected from alkyl).

Two occurrences of ^JR on the same atom, together with the atoms to which they are attached, a 3-6 membered aromatic having 0-2 heteroatoms selected from oxygen, nitrogen or sulfur, or 36. The compound according to any one of claims 27 to 35, or a pharmaceutically acceptable salt or prodrug thereof , which forms a non-aromatic ring.

^JP is a halo, —C _1-4 alkyl, or a 3-6 membered non-aromatic ring, having 0-2 heteroatoms selected from oxygen, nitrogen or sulfur, 45. A compound according to any one of claims 40 to 44 or a pharmaceutically acceptable salt or prodrug thereof .

J ^P is selected from pyrrolidinyl or oxetanyl compound or a pharmaceutically acceptable salt or prodrug of claim 45.

R ³ is T, a compound or a pharmaceutically acceptable salt or prodrug according to any one of claims 11 to 13.

T is — (C _1-4 alkyl), — (C _1-4 alkyl) N (C _1-4 alkyl) ₂ , — (C _1-3 alkyl) O (C _1-2 alkyl) N (C _{1 to 3} _alkyl) 2, - _{(C 1 to 4} alkyl) OH, - _{(C 1 to 4} alkyl) NH ₂ or - is independently selected from _{(C 1 to 4} alkyl) _{O (C 1 to 4} alkyl) 48. The compound of claim 47, or a pharmaceutically acceptable salt or prodrug thereof .

^49. The compound of claim 48, or a pharmaceutically acceptable salt or prodrug thereof , wherein ^JLT is halo or _C1-3alkyl .

A is

2. The compound according to claim 1 or a pharmaceutically acceptable salt or prodrug thereof selected independently from

51. The compound according to claim 50, or a pharmaceutically acceptable salt or prodrug thereof , wherein p is 0.

51. The compound according to claim 50, wherein p is 1, or a pharmaceutically acceptable salt or prodrug thereof .

R ⁴ is independently selected from C _{1 to 4} alkyl or halo, the compound or a pharmaceutically acceptable salt or prodrug of claim 52.

R ⁴ is independently selected from methyl or fluoro, a compound or a pharmaceutically acceptable salt or prodrug of claim 52.

R ³ is - _(L) is a n -Q ^1, compound, or a pharmaceutically acceptable salt or prodrug according to any one of claims 50 to 54.

56. The compound according to claim 55, wherein n is 0, or a pharmaceutically acceptable salt or prodrug thereof .

56. The compound according to claim 55, wherein n is 1, or a pharmaceutically acceptable salt or prodrug thereof .

L is independently selected from C _{1 to 4} alkyl, compound, or a pharmaceutically acceptable salt or prodrug of claim 57.

Q ¹ is a phenyl, a compound or a pharmaceutically acceptable salt or prodrug according to any one of claims 55 to 58.

Q ¹ is are independently selected from 3-6 membered carbocyclyl or 4-6-membered heterocyclyl, A compound according to any one of claims 55 to 58 or a pharmaceutically acceptable salt or pro Drag .

Q ¹ is cyclopropyl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyran, is independently selected from dihydropyran or tetrahydropyridine compound according to claim 60 or a pharmaceutically acceptable salt or prodrug thereof .

Q ¹ is a 5-6 membered heteroaryl, a compound or a pharmaceutically acceptable salt or prodrug according to any one of claims 55 to 58.

Q ¹ is, pyrazolyl, independently selected from pyridinyl or pyrimidinyl, the compound or a pharmaceutically acceptable salt or prodrug of claim 62.

J ^Q is independently selected from C _1-6 aliphatic chains, and up to 3 methylene units of the aliphatic chain are optionally -O-, -NR- or -C (O)-. 64. The compound according to any one of claims 55 to 63, or a pharmaceutically acceptable salt or prodrug thereof , which is replaced.

J ^Q is, -C (O) -, - C (O) are independently selected from _{C 1 to 4} alkyl or _{C 1 to 4} alkyl, acceptable compound or a pharmaceutically according to claim 64 Salt or prodrug .

66. The compound of claim 65, or a pharmaceutically acceptable salt or prodrug thereof , wherein ^JQ is methyl.

66. The compound according to claim 65, or a pharmaceutically acceptable salt or prodrug thereof , wherein ^JR is independently selected from piperidinyl or piperazinyl.

J ^P is independently selected from oxetanyl or azetidinyl, compound, or a pharmaceutically acceptable salt or prodrug of claim 67.

R ³ is T, a compound or a pharmaceutically acceptable salt or prodrug according to any one of claims 50 to 54.

T is a C _1-6 aliphatic chain, and up to 3 methylene units of the aliphatic chain are optionally replaced with —O—, —NR— or —C (O) —. Item 70. The compound according to Item 69, or a pharmaceutically acceptable salt or prodrug thereof .

_72. The compound according to claim 70, or a pharmaceutically acceptable salt or prodrug thereof, wherein T _is- ( _C1-3alkyl ) O ( _C1-3alkyl ).

The compound is

72. The compound according to any one of claims 1 to 71, or a pharmaceutically acceptable salt or prodrug thereof , selected independently from

75. A pharmaceutical composition comprising a compound according to any one of claims 1 to 72 or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.

Compound or a pharmaceutically including acceptable induced body composition for treating cancer in a patient according to any one of claims 1 to 72.

Characterized in that additional therapeutic agent selected independently from D NA damaging agent is administered to said patient; said additional therapeutic agent is suitable for diseases performing treatment; and said additional therapeutic agent is a single Luke is administered together with said compound as an dosage form, or the said compound, characterized in that that will be administered separately as part of a multiple dosage form composition according to claim 74.

76. The composition of claim 75, wherein the DNA damaging agent is a selected chemotherapeutic agent or radiation treatment.

The DNA damaging agent is independently selected from ionizing radiation, radioactive neocarzinostatin, platinum preparation, topo I inhibitor, topo II inhibitor, antimetabolite, alkylating agent, alkyl sulfonate or antibiotic. 77. The composition of claim 76.

76. The composition of claim 75, wherein the DNA damaging agent is independently selected from ionizing radiation, platinum formulations, topo I inhibitors, topo II inhibitors, antimetabolites, alkylating agents or alkyl sulfonates.

76. The composition of claim 75, wherein the DNA damaging agent is independently selected from ionizing radiation, platinum preparations, topo I inhibitors, topo II inhibitors or antibiotics.

The platinum preparation is independently selected from cisplatin, oxaliplatin, carboplatin, nedaplatin, lovatoplatin, triplatin tetranitrate, picoplatin, satraplatin, ProLindac and alloplatin; The topo II inhibitor is selected from etoposide, daunorubicin, doxorubicin, aclarubicin, epirubicin, idarubicin, amrubicin, pirarubicin, valrubicin, zorubicin and teniposide; Statin, cladribine, clofarabine, fludarabine, thioguanine, merca Selected from toppurin, fluorouracil, capecitabine, tegafur, carmofur, floxuridine, cytarabine, gemcitabine, azacitidine and hydroxyurea; the alkylating agent is mechloretamine, cyclophosphamide, ifosfamide, trophosphamide, chlorambucil, melphalan, prednisotin , Uramustine, estramustine, carmustine, lomustine, semustine, hotemustine, nimustine, ranimustine, streptozocin, busulfan, mannosulfan, treossulfan, carbocon, thiotepa, triadicon, triethylenemelamine, procarbazine, dacarbazine, temozolomide , Mitobronitol, actinomycin, bleomycin, my It is selected from hygromycin and plicamycin The composition of claim 76.

The platinum preparation is independently selected from cisplatin, oxaliplatin, carboplatin, nedaplatin or satraplatin; the topo I inhibitor is selected from camptothecin, topotecan, irinotecan / SN38, rubitecan; and the topo II inhibitor is from etoposide The antimetabolite is selected from methotrexate, pemetrexed, thioguanine, fludarabine, cladribine, cytarabine, gemcitabine, 6-mercaptopurine or 5-fluorouracil; the alkylating agent is nitrogen mustard, nitrosourea, triazene, Selected from alkyl sulfonates, procarbazine or aziridine; said antibiotic is hydroxyurea, anthracycline, anthracenedione or strepto It is selected from Seth family composition of claim 78.

79. The composition of claim 78, wherein the DNA damaging agent is independently selected from a platinum formulation or ionizing radiation.

79. The composition of claim 78, wherein the antimetabolite is gemcitabine.

79. The composition of claim 78, wherein the DNA damaging agent is ionizing radiation.

79. The composition of claim 78, wherein the DNA damaging agent is a platinum formulation independently selected from cisplatin or carboplatin.

79. The composition of claim 78, wherein the DNA damaging agent is a topo II inhibitor selected from etoposide.

79. The composition of claim 78, wherein the DNA damaging agent is an alkylating agent selected from temozolomide.

79. The composition of claim 78, wherein the DNA damaging agent is independently selected from one or more of the following: cisplatin, carboplatin, gemcitabine, etoposide, temozolomide or ionizing radiation.

The cancer is the following cancer: oral cavity: buccal oral cavity, lip, tongue, mouth, pharynx; heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, Fibroma, lipoma and teratoma; lung: bronchial cancer (squamous or epidermis, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiole) cancer, bronchial adenoma, sarcoma, Lymphoma, cartilaginous hamartoma, mesothelioma; digestive system: esophagus (squamous cell carcinoma, larynx, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (conduit gland , Insulinoma, glucagon-producing tumor, gastrin-producing tumor, carcinoid tumor, VIP-producing tumor), small bowel or small intestine
intestine) (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel or large intestine (adenocarcinoma, tubular adenoma) , Villous adenoma, hamartoma, leiomyoma), colon, colon-rectum, colorectal; rectum, urogenital tract: kidney (adenocarcinoma, Wilms tumor [nephroblastoma], lymphoma), bladder and urethra (squamous cells) Cancer, transitional cell cancer, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testicles (seminomas, teratomas, embryonic cancer, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell cancer, Fibroma, fibroadenoma, adenoid tumor, lipoma); liver: hepatocellular carcinoma (hepatocellular carcinoma), bile duct cancer, hepatoblastoma, hemangiosarcoma, hepatocellular adenoma, hemangioma, bile tract; bone: bone Original sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing sarcoma, malignant phosphorus (Reticulosarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteoclon fromma (osteochondroma), benign chondroma, chondroblastoma, chondromyxoma, osteoid osteoma Nervous system: skull (osteomas, hemangiomas, granulomas, xanthomas, osteoarthritis), meninges (meningiomas, meningosarcoma, gliomatosis), brain (astrocytic cells) , Medulloblastoma, glioma, ependymoma, germinoma [pineoblastoma], glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), Spinal neurofibroma, meningioma, glioma, sarcoma); gynecology / female: uterus (endometrial cancer), cervix (cervical cancer, preneoplastic cervical dysplasia), ovary (Ovarian cancer [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-capsular cell carcinoma, Sertoli Leydig cell carcinoma, anaplastic germoma, malignant teratoma), vulva (Squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, grape sarcoma (fetal rhabdomyosarcoma), fallopian tube (carcinoma) ), Breast; skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi sarcoma, keratoacanthoma, dysplastic nevi, lipoma, angioma, dermal fibroma, keloid, psoriasis, thyroid: Papillary thyroid cancer, follicular thyroid cancer; medullary thyroid cancer, multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, familial medullary thyroid cancer, pheochromocytoma, paraganglioma 89. A composition according to any one of claims 84 to 88, wherein the composition is a solid tumor selected from: adrenal gland: neuroblastoma.

90. The composition of claim 89, wherein the cancer is selected from lung or pancreatic cancer.

89. The composition according to any one of claims 84 to 88, wherein the cancer is selected from lung cancer, head and neck cancer, pancreatic cancer, stomach cancer or brain cancer.

Non-small cell lung cancer, small cell lung cancer, pancreatic cancer, biliary tract cancer, head and neck cancer, bladder cancer, colorectal cancer, glioblastoma, esophageal cancer, breast cancer, hepatocytes 89. The composition according to any one of claims 84 to 88, selected from cancer or ovarian cancer.

90. The composition of claim 89, wherein the additional therapeutic agent is gemcitabine and the cancer is pancreatic cancer.

A compound or composition for treating pancreatic cancer comprising a pharmaceutically acceptable salt or prodrug according to any one of 請 Motomeko 1-72, the composition, gemcitabine A composition characterized by being administered to a patient in combination with radiation therapy or an additional therapeutic agent selected from both gemcitabine and radiation therapy .

Comprising a compound or a pharmaceutically acceptable salt or prodrug according to any one of 請 Motomeko 1-72, sensitization of pancreatic cancer cell to a cancer therapy selected from chemotherapeutic or radiation therapy A composition for increasing sex , wherein the composition is administered to a patient .

96. The composition of claim 95, wherein the chemotherapy is gemcitabine.

96. The composition of claim 95, wherein the cancer treatment is gemcitabine.

96. The composition of claim 95, wherein the cancer treatment is radiation.

96. The composition of claim 95, wherein the cancer treatment is gemcitabine and radiation.

請 compound according to any one of Motomeko 1-72 or a pharmaceutically acceptable salt or prodrug including, compositions for inhibiting the phosphorylation of Chk1 (Ser345) in pancreatic cancer cells A composition, characterized in that the composition is administered in combination with gemcitabine (100 nM) and / or radiation (6 Gy) .

Comprising a compound or a pharmaceutically acceptable salt or prodrug according to any one of 請 Motomeko 1-72, there in a composition for sensitizing pancreatic cancer cells to chemoradiation The composition is administered in combination with chemoradiotherapy .

102. The composition of claim 101, wherein the chemoradiotherapy is gemcitabine and radiation.

Comprising a compound or a pharmaceutically acceptable salt or prodrug according to any one of 請 Motomeko 1-72, hypoxic pancreatic cancer cells a composition for the radiation sensitization The composition is administered in combination with radiation therapy .

Comprising a compound or a pharmaceutically acceptable salt or prodrug according to any one of 請 Motomeko 1-72, a composition for the sensitizing hypoxic pancreatic cancer cells, A composition wherein the composition is administered in combination with chemotherapy .

105. The composition according to any one of claims 101 to 104, wherein the cancer cells are PSN-1, MiaPaCa-2 or PancM cancer cells.

It comprises a compound or a pharmaceutically acceptable salt or prodrug according to any one of 請 Motomeko 1-72, a composition for destroying damage induced cell cycle checkpoint, the composition The composition is administered in combination with radiation therapy and / or gemcitabine .

請 compound according to any one of Motomeko 1-72 or a pharmaceutically acceptable comprising a salt or prodrug composition for inhibiting the repair of DNA damage by homologous recombination in pancreatic cancer cells A composition, wherein the composition is administered in combination with radiation therapy and / or gemcitabine .

Wherein said compound characterized in that it is administered to a patient, the composition according to any one of claims 101 to 107.

Wherein said compound characterized in that it is administered to pancreatic cancer cells, the composition according to any one of claims 101 to 107.

110. The composition of claim 109, wherein the pancreatic cancer cells are derived from a pancreatic cell line selected from PSN-1, MiaPaCa-2 or Panc-1.

A composition for treating non-small cell lung cancer, comprising the compound according to any one of claims 1 to 72 or a pharmaceutically acceptable salt or prodrug thereof , wherein the composition comprises An additional therapeutic agent of: A composition characterized in that it is administered in combination with one or more of cisplatin or carboplatin, etoposide and ionizing radiation.

請 Motomeko comprising a compound or a pharmaceutically acceptable salt or prodrug according to any one of 1 to 72, a composition according to claim 111, wherein the composition, cisplatin or carboplatin A composition characterized in that it is administered in combination with etoposide and ionizing radiation.

請 compound according to any one of Motomeko 1-72 or a pharmaceutically acceptable salt or prodrug including a composition for promoting cell death in cancer cells, the composition A composition, wherein the product is administered to a patient .

Comprising a compound or a pharmaceutically acceptable salt or prodrug according to any one of 請 Motomeko 1-72, a composition for preventing cell repair from DNA damage, the composition Is administered to a patient .

A composition for inhibiting ATR in a biological sample comprising the compound according to any one of claims 1 to 72 or a pharmaceutically acceptable salt or prodrug thereof , wherein the composition comprises A composition, characterized in that it is brought into contact with the biological sample.

116. The composition of claim 115, wherein the biological sample is a cell.

Comprising a compound or a pharmaceutically acceptable salt or prodrug according to any one of 請 Motomeko 1-72, the cells a composition for the sensitization to DNA damaging agents, the A composition, wherein the composition is administered to a patient .

118. The composition according to any one of claims 74 to 117, wherein the cell is a cancer cell having a defect in an ATM signal cascade.

119. In claim 118, wherein the deficiency is a change in expression or activity of one or more of the following: ATM, p53, CHK2, MRE11, RAD50, NBS1, 53BP1, MDC1, H2AX, MCPH1 / BRIT1, CTIP or SMC1 The composition as described.

119. The composition of claim 118, wherein the deficiency is a change in the expression or activity of one or more of the following: ATM, p53, CHK2, MRE11, RAD50, NBS1, 53BP1, MDC1 or H2AX.

118. The composition according to any one of claims 74 to 117, wherein the cell is a cancer cell that expresses a DNA-damaged oncogene.

Said cancer cell is expressed by one or more of the following: K-Ras, N-Ras, H-Ras, Raf, Myc, Mos, E2F, Cdc25A, CDC4, CDK2, cyclin E, cyclin A and Rb 122. The composition of claim 121, having a change in activity.

118. The composition according to any one of claims 74 to 117, wherein the cancer, cancer cell or cell has a base excision repair protein deficiency.

The base excision repair protein is UNG, SMUG1, MBD4, TDG, OGG1, MYH, NTH1, MPG, NEIL1, NEIL2, NEIL3 (DNA glycosylase); APE1, APEX2 (AP endonuclease); LIG1, LIG3 (DNA ligase I and III); XRCC1 (LIG3 accessory); PNK, PNKP (polynucleotide kinase and phosphatase); PARP1, PARP2 (poly (ADP-ribose) polymerase); PolB, PolG (polymerase); FEN1 (endonuclease) or aplataxin, 124. The composition of claim 123.

126. The composition of claim 124, wherein the base excision repair protein is PARP1, PARP2, or PolB.

126. The composition of claim 125, wherein the base excision repair protein is PARP1 or PARP2.

127. The composition of any one of claims 74 to 126 , wherein an additional therapeutic agent is administered to the patient, and the agent inhibits or modulates a base excision repair protein.

The base excision repair protein is UNG, SMUG1, MBD4, TDG, OGG1, MYH, NTH1, MPG, NEIL1, NEIL2, NEIL3 (DNA glycosylase); APE1, APEX2 (AP endonuclease); LIG1, LIG3 (DNA ligase I and III); XRCC1 (LIG3 accessory); PNK, PNKP (polynucleotide kinase and phosphatase); PARP1, PARP2 (poly (ADP-ribose) polymerase); PolB, PolG (polymerase); FEN1 (endonuclease) or aplataxin 128. The composition of claim 127.

129. The composition of claim 128, wherein the base excision repair protein is selected from PARP1, PARP2, or PolB.

130. The composition of claim 129, wherein the base excision repair protein is selected from PARP1 or PARP2.

The drugs include olaparib (also known as AZD2281 or KU-0059436), iniparib (also known as BSI-201 or SAR240550), veriparib (also known as ABT-888), lucaparib (as PF-01367338). 132. The composition according to any one of claims 129 or 130 , which is also selected from CEP-9722, INO-1001, MK-4827, E7016, BMN673 or AZD2461.

Compounds of formula I:

Wherein the compound of formula 6:

Comprising reacting under appropriate conditions to form an amide bond, wherein:
J is H or Cl;
Process R ^1, ^{R 2} and A are as defined in claim 1 to 72.

Compound of formula 6:

A compound of formula 5:

Is reacted under suitable conditions further comprises the step of preparing by forming an activated ester process according to claim 13 2.

Compounds of formula I:

Wherein the compound of formula 5:

Reacting under appropriate conditions to form an amide bond,
A process wherein R ¹ , R ² and A are as defined in claims 1-72.

Compound of formula 5:

A compound of formula 4:

Further comprising the step of preparing by reacting under appropriate deprotection conditions, the process according to any one of claims 13 2-13 4.

Compound of formula 4:

A compound of formula 3:

It is reacted with a suitable condensation conditions further comprising the step of preparing by forming a pyrimidine ring, The process of claim 13 5.

Compound of formula 3:

A compound of formula 2:

Further comprising the step of preparing by forming allowed by pyrazole ring by reacting with a suitable condensation conditions, The process of claim 13 6.

Compound of formula 2:

A compound of formula 1:

Further comprises the step of preparing by reacting with a suitable anion condensation conditions, The process of claim 13 7.

Compounds of formula I:

Wherein the compound of formula 9:

Reacting under suitable condensation conditions to form a pyrimidine ring,
A process wherein R ¹ , R ² and A are as defined in claims 1-72.

Compound of formula 9:

A compound of formula 8:

Further comprising the step of preparing by forming allowed by pyrazole ring by reacting with a suitable condensation conditions, The process of claim 13 7.

Compound of formula 8:

A compound of formula 7:

Further comprising the step of preparing by forming the allowed amide bond under suitable conditions, The process of claim 13 8.